Photochemical cycloaddition of mono-, 1,1-, and 1,2-disubstituted olefins to a chiral 2(5H)-furanone. Diastereoselective synthesis of (+)-lineatin

Article abstract of DOI:10.1021/jo800970u

(Chemical Equation Presented) The photochemical [2 + 2] cycloaddition of (S)-4-methyl-5-O-pivaloyloxymethyl-2(5H)-furanone, 5, to vinyl acetate, vinyl pivalate, tert-butyl vinyl ether, 1,1-diethoxyethylene, and (Z)- and (E)-1,2-dichloroethylene has been studied. A practical synthesis of (+)-lineatin from 5 has been developed via the functionalized cyclobutane 6.

Full text of DOI:10.1021/jo800970u

Photochemical Cycloaddition of Mono-, 1,1-, and 1,2-Disubstituted
Olefins to a Chiral 2(5H)-Furanone. Diastereoselective Synthesis of
(+)-Lineatin
Marta Racamonde, Ramon Alibe´s,* Marta Figueredo, Josep Font, and Pedro de March
Departament de Qu´ımica, UniVersitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
ramon.alibes@uab.cat
ReceiVed May 6, 2008
The photochemical [2 + 2] cycloaddition of (S)-4-methyl-5-O-pivaloyloxymethyl-2(5H)-furanone, 5, to
vinyl acetate, vinyl pivalate, tert-butyl vinyl ether, 1,1-diethoxyethylene, and (Z)- and (E)-1,2-
dichloroethylene has been studied. A practical synthesis of (+)-lineatin from 5 has been developed via
the functionalized cyclobutane 6.
Introduction
envisioned that this advanced precursor would be obtained
through a more straightforward route involving oxidation of the
cyclobutane triol 6, which in turn would be also prepared from
4 by deoxygenation of the secondary alcohol. In both synthetic
pathways, a major challenge was the construction of the
functionalized cyclobutane with the correct regio- and stereo-
chemistry. It was envisaged that the pivotal cyclobutane
intermediate 4 could be obtained by a [2 + 2] photochemical
reaction involving lactone 5 and a suitable substituted alkene.
Herein, we report in detail our investigations on the photo-
chemical [2 + 2] cycloaddition of 2(5H)-furanone 5 to several
enol esters and enol ethers, to ketene diethyl ketal, and to (Z)-
and (E)-1,2-dichloroethylene. Also, an improved synthesis of
(+)-lineatin is reported.
The cyclobutane monoterpene (+)-lineatin, 1 (Scheme 1),
isolated in 1977,1 is the main component of the female-produced
pheromone of the ambrosia beetle, Trypodendron lineatum
Olivier, which is responsible for coniferous forest infestation
in Europe and North America. The natural occurrence, biological
activity, and unusual structural features of lineatin have attracted
considerable synthetic interest that has culminated in various
synthesis of (+)-1, with total yields between 0.2 and 4%.2 In
most of these syntheses, the enantiomeric purity depends on
the optical resolution of a key intermediate.
We have recently accomplished a formal synthesis of (+)-1
in an overall yield of 14% starting from the suitable chiral 2(5H)-
furanone 5.3 Our synthesis contemplated a late oxidation step
of the bicyclic ether intermediate 3 to furnish the keto lactone
2, which had already been converted into 1.2e Compound 3 was
readily accessed from the functionalized cyclobutane 4 via
oxycyclization and deoxygenation. Due to the high volatility
of 3, concentration of its solution or its purification always has
caused a considerable loss of product. This fact prompted us to
consider a modified strategy for the preparation of the crucial
six-membered lactone intermediate 2. The alternative synthesis
Results and Discussion
Photochemical Study. When this work was initiated, we
were not aware of any photochemical addition of vinyl esters
or ethers to chiral 2(5H)-furanones. Accordingly, our first task
was to study the photochemical reaction of 5 to unsymmetrical
oxyalkenes 7, which was visualized as a convenient method to
prepare 4, provided the reaction would proceed with the desired
stereo- and regiochemical control.
Considering the head-to-head (HH)/head-to-tail (HT) regio-
selectivity, the anti/syn facial approaches, and the exo/endo
stereoselectivity, this photochemical reaction could lead to the
formation of up to eight isomers (Scheme 2). In most examples
of the [2 + 2] photocycloaddition of cyclic enones to electron-
rich alkenes, the formation of HT adducts is favored, although
the regioselectivity of the process results from a balance between
(1) MacConnell, J. G.; Borden, J. H.; Silverstein, R. M.; Stokkink, E. J. Chem.
Ecol. 1977, 3, 549–561.
(2) (a) Mori, K.; Sasaki, M. Tetrahedron 1980, 36, 2197–2208. (b) Slessor,
K. N.; Oehlschlager, A. C.; Johnston, B. D.; Pierce, H. D.; Grewal, S. K.;
Wickremesinghe, L. K. G. J. Org. Chem. 1980, 45, 2290–2297. (c) Mori, K.;
Uematsu, T.; Minobe, M.; Yanagi, K. Tetrahedron 1983, 39, 1735–1743. (d)
Kandil, A. A.; Slessor, K. N. J. Org. Chem. 1985, 50, 5649–5655. (e) Mori, K.;
Nagano, E. Liebigs Ann. Chem. 1991, 341–344.
(3) Alibe´s, R.; de March, P.; Figueredo, M.; Font, J.; Racamonde, M.; Parella,
T. Org. Lett. 2004, 6, 1449–1452.
5944 J. Org. Chem. 2008, 73, 5944–5952
10.1021/jo800970u CCC: $40.75 2008 American Chemical Society
Published on Web 07/08/2008

Photochemical Cycloaddition of Disubstituted Olefins
SCHEME 1. Retrosynthetic Analysis of (+)-Lineatin, (+)-1
SCHEME 2. [2 + 2] Photochemical Cycloaddition of 5 to
7a-c
the three major adducts, the HT-anti 8c endo and 8c exo and
the HH-anti 10c endo, were identified. In all the reactions
studied, analysis of the mixture by GC-MS indicated that all
the compounds within a series possessed identical masses and
fragmentation patterns consistent with the expected cycloadducts.
The regio- and stereochemistry of the major photocycload-
ducts could be assigned with the help of 1D and 2D NMR
experiments. The regioselectivity of the addition was established
by analysis of the 13C NMR spectra wherein the signal of the
carbon atom C-5 in the HT isomers (8a-c) appears at lower
field (δ ∼ 47-50) compared to the HH isomer 10c (δ ∼ 36),
due to the deshielding effect of the cyclobutane oxy-substituent.
The opposite trend is observed in the chemical shift of C-1 (δ
∼ 38-40 in the HT isomers and δ ∼ 53 in the HH isomer).5
The 13C NMR spectra also give information about the facial
selectivity. It is known from previous work6 that the signal of
the angular carbon methyl group, because of the larger “steric
compression” due to the cis arrangement of the methyl and the
pivaloyloxymethyl substituents in the anti isomers, appears high
field shifted (∼18 ppm) compared to the syn isomers (∼21
ppm). Thus, the photoadducts 8a-c and 10c endo show δ
around 18 ppm, while the isomers 8a and 8c exo, in which the
angular methyl group is even more sterically hindered, exhibit
δ around 11 ppm, indicating that all the isolated adducts come
electronic and steric effects. Thus, it has been reported that
modifications in either the substrates or the reaction conditions
can modulate the regiochemical outcome of the photochemical
process.4 In the present study, we expected that both the
pivaloyloxymethyl and ꢀ-methyl substituents of the lactone
could influence the regio- and stereochemical outcome of the
cycloaddition, favoring the formation of the anti-HH isomers
10 endo/exo.
Irradiation of an acetone solution of lactone 5 and a 10-fold
excess of vinyl acetate, 7a, with a high-pressure mercury lamp
through a Pyrex filter for 3 h at -20 °C resulted in the formation
of a mixture (28:25:15:14:10:8) of six of the eight possible
isomers in 95% global yield, among which, after repeated
column chromatography, only the main photoadducts HT-anti,
8a exo and 8a endo (Figure 1), could be identified (vide infra).
In search for a better selectivity, we decided to employ the more
sterically demanding olefins vinyl pivalate, 7b, and tert-butyl
vinyl ether, 7c. Thus, the photoreaction of 5 with pivalate 7b
furnished a mixture (44:13:12:11:11:5:4) of seven cycloadducts
in 82% overall yield, from where the major cycloadduct HT-
anti, 8b endo, could be isolated by column chromatography.
Finally, irradiation of 5 with the ether 7c, in which the bulky
substituent is closer to the double bond, gave a 29:22:19:12:9:
8:1 mixture of seven cycloadducts in 87% yield, from which
(4) (a) Lange, G. L.; Decicco, C.; Lee, M. Tetrahedron Lett. 1987, 28, 2833–
2836. (b) Lange, G. L.; Organ, M. G.; Lee, M. Tetrahedron Lett. 1990, 31,
4689–4692. (c) Suishu, T.; Shimo, T.; Somekawa, K. Tetrahedron 1997, 53,
3545–3556. (d) Bach, T. Synthesis 1998, 683–703.
(5) Rustullet, A.; Alibe´s, R.; de March, P.; Figueredo, M.; Font, J. Org. Lett.
2007, 9, 2827–2830.
FIGURE 1. Major photocycloadducts from the [2 + 2] photochemical
cycloaddition of 2(5H)-furanone 5 to olefins 7a-c and selected NOE
difference experiments.
(6) Alibe´s, R.; Bourdelande, J. L.; Font, J.; Gregori, A.; Parella, T.
Tetrahedron 1996, 52, 1267–1278.
J. Org. Chem. Vol. 73, No. 15, 2008 5945

Racamonde et al.
SCHEME 3. [2 + 2] Photochemical Cycloaddition of 5 to 12
SCHEME 4. [2 + 2] Photochemical Cycloaddition of 5 to
1,2-Dichloroethylene and Subsequent Zn-Promoted
Dechlorination
TABLE 1. [2 + 2] Photocycloaddition of 2(5H)-Furanone 5 to
Ketene Ketal 12
triplet 1,4-biradical intermediate that closes to furnish a HT
photoadduct.8
yield
13:14:
HT:HH anti:synb
entry
solvent
acetone
acetonitrile 35 min
ether
t
(%)a (15+16)
(%)
(%)
In view of the former results, we considered the possibility
of introducing the functionality present in the cyclobutane ring
of the target compound 4 from a double bond in a regioselective
fashion. Initially, we considered the straightforward preparation
of the anti cyclobutene 17 (Scheme 4) by photochemical
cycloaddition of 5 to acetylene,9 but this reaction occurred in
low yield (35%) and scarce anti facial selectivity (6%).
Therefore, a more convenient, two-step protocol based on the
photochemical [2 + 2] reaction of lactone 5 with either (E)- or
(Z)-1,2-dichloroethylene, (E)- or (Z)-19, followed by Zn-
promoted dechlorination was applied.10
Accordingly, an acetone solution of lactone 5 and a 5-fold
excess of (E)-19 was irradiated through a Pyrex filter with a
high-pressure mercury lamp for 10 h at -20 °C, affording a
mixture of seven isomeric dichlorocycloadducts (as evidenced
by GC-MS and NMR analysis of the crude product) in 32%
combined yield (Table 2, entry 1). Similar results were found
by using (Z)-19 (entry 2). However, when the photochemical
reaction of 5 with (E)-19 was performed in acetonitrile, after
10 h of irradiation through a quartz filter, a mixture of seven
isomers was obtained in 76% yield (entry 3). A faster, cleaner,
and better yielding reaction (89%) was achieved with (Z)-19 in
acetonitrile (entry 4).
To get a deeper insight into the factors controlling the
stereochemistry of these photoadditions, the major dichlorocy-
cloadducts were isolated by repeated column chromatography.
Stereochemical assignments of the individual isomers were
assessed by detailed analysis of their 1H and 13C NMR spectra
and by NOE difference experiments (Figure 2).
It was concluded that the photocycloaddition proceeds in a
highly diastereoselective manner affording mainly anti cycload-
ducts. Interestingly, in the reactions sensitized by acetone,
identical ratio of cycloadducts was obtained from either (Z)- or
(E)-19. By contrast, when the reactions were performed under
direct excitation (entries 3 and 4), the ratio of adducts was
different. Considering exclusively the anti cycloadducts 21-24,
it can be observed that starting from (E)-19, the trans relative
configuration of the chlorine atoms is slightly favored over the
cis (57:43), and from (Z)-19, the predominance of the trans
1
2
3
4
8 h
25
85
80
69
64:32:4
63:31:6
51:42:7
47:46:7
96:4
94:6
93:7
93:7
66:34
67:33
55:45
50:50
1.5 h
1.7 h
hexane
a Isolated yield of the mixture of adducts after column chromato-
graphy purification. b The anti/syn ratio of the HT isomers.
from antifacial approaches of the reactants. The results of NOE
difference experiments provided additional support to the
stereochemical assignment (Figure 1).
The complexity of the mixtures obtained from the photore-
action of vinyl esters and ether to furanone 5 and the HT
regioselectivity of the addition, which is contrary to our synthetic
interests, led us to consider the alternative cycloaddition of 1,1-
diethoxyethylene, 12, to lactone 5, wherein the number of
possible cycloadducts is limited to four (Scheme 3).7
First, irradiation of 5 and a 5-fold excess of 12 was carried
out in acetone through a Pyrex filter at -20 °C, and after 8 h,
a mixture of the four possible cycloadducts 13-16 was isolated
in only 25% yield (Table 1, entry 1). When the photoreaction
was performed in acetonitrile through a quartz filter, the overall
yield increased to 85% (entry 2). Unfortunately, chromato-
graphic separation of the major adducts was not possible, and
NMR analysis of the mixture had to be performed. The HT
regiochemistry of the major adducts 13 and 14 was established
by HMBC experiments, wherein a correlation between the acetal
carbon atom C-6 and proton H-4 is observed in both isomers,
while the anti/syn relative configuration was determined through
the chemical shift of the angular methyl group in the 13C NMR
spectra, as indicated previously.
Next, the reaction was also performed in ether and hexane
to study the influence of the solvent polarity (entries 3 and 4).
It was found that the regioselectivity remained essentially
unaltered, while the facial selectivity decreased from 67:33 in
acetonitrile to 55:45 and 50:50 in ether and hexane, respectively.
As in the case of the vinyl esters and ethers, the photocy-
cloaddition of the ketene ketal afforded preferentially the
undesired HT isomers. These results indicate that the electronic
effects prevail over the steric effects in determining the
regioselectivity of the process. The observed regioselectivity is
consistent with a mechanism in which formation of the initial
bond occurs selectively between C-3 of the 2(5H)-furanone
triplet and the less substituted end of the alkene, delivering a
(8) Broeker, J. L.; John, E.; Eksterowicz, J. E.; Anna, J.; Belk, A. J.; Houk,
K. N. J. Am. Chem. Soc. 1995, I17, 1847–1848.
(9) Alibe´s, R.; de March, P.; Figueredo, M.; Font, J.; Fu, X.; Racamonde,
M.; Alva´rez-Larena, A.; Piniella, J. F.; Parella, T. J. Org. Chem. 2003, 68, 1283–
1289.
(7) (a) Kosugi, H.; Sekiguchi, S.; Sekita, R.; Uda, H. Bull. Chem. Soc. Jpn.
1976, 49, 520–528. (b) Fillol, L.; Miranda, M. A.; Morera, I. M.; Sheikh, H.
Heterocycles 1990, 31, 751–782, and references cited therein.
(10) Alibe´s, R.; de March, P.; Figueredo, M.; Font, J.; Racamonde, M.;
Rustullet, A.; Alva´rez-Larena, A.; Piniella, J. F.; Parella, T. Tetrahedron Lett.
2003, 44, 69–71.
5946 J. Org. Chem. Vol. 73, No. 15, 2008

Photochemical Cycloaddition of Disubstituted Olefins
TABLE 2. [2 + 2] Photochemical Cycloaddition of 5 to (E)- and (Z)-19
entry
olefin
filter
solvent
t
yield (%)a
21:22:23:24:25:others (%)b, c
anti:syn (%)
anti cis:trans (%)
1
2
3
4
(E)-19
(Z)-19
(E)-19
(Z)-19
Pyrex
Pyrex
quartz
quartz
acetone
acetone
acetonitrile
acetonitrile
10 h
8 h
12 h
7 h
32
45
76
89
33:26:10:18:8:4:1
35:25:10:16:7:5:2
25:23:7:29:11:4:1
35:28:14:11:6:5:1
87:13
86:14
84:16
88:12
32:68
30:70
43:57
29:71
a Isolated yield. b Isomer ratio from GC analysis of the crude product. c Others are syn cycloadducts whose configuration could not be assigned.
SCHEME 5
Synthesis of (+)-Lineatin. With the anti cycloadduct 17 on
hand, the synthesis of the pheromone was continued by treating
it with an excess of methyl lithium in THF at -78 °C, followed
by reaction with acetone containing a catalytic amount of
p-toluenesulfonic acid at room temperature to deliver the
acetonide 26 in 80% overall yield (Scheme 5).
We initially planned to use the cyclobutene π bond to set up
the O-functionality at C-2′ by a hydroboration process, in which
the hydroxyl or dioxolane oxygen atoms could direct the
approach of the hydroborating agent to the endo hindered face
of the olefin.17 In practice, treatment of 26 with BH3-THF
provided, after oxidation with H2O2, a chromatographically
separable 20:15:27:38 mixture of the four possible isomeric
alcohols 27-30 in 89% yield (Figure 2). The regio- and
stereochemistries of these cyclobutanols were assigned by 1D
and 2D NMR spectroscopy. The connectivity was established
by HMBC experiments, wherein one of the methylene protons
H-4 correlates with the carbon atom C-4′ for isomers 27 and
29 and with C-1′′ for isomers 28 and 30. The configuration at
the stereogenic center C-1 was inferred by the NOESY
correlations shown in Figure 3. These assignments reflect the
lack of regioselectivity of the process and a moderate preference
of the borane to attack from the less hindered side of the double
bond (65:35), which is opposite to the potentially directing
oxygen atoms of the substrate. Moreover, the double bond of
26 resisted hydroboration by other more sterically demanding
reagents, such as disiamylborane and 9-borabicyclo[3.3.1]nonane
(9-BBN).
FIGURE 2. Dichlorocycloadducts 21-25 and selected NOE difference
experiments.
relationship is even higher (71:29), indicating that the stereo-
chemistry of the alkene component is lost in the reaction
course.11,12
Next, we studied the reductive elimination of the dichloro-
cycloadducts under different reaction conditions. Attempted
dechlorination with activated Zn in refluxing glacial acetic acid,
acetonitrile,13 or dry ethanol14 met with failure, returning
unaltered starting material. Treatment of the mixture of dichlo-
rocycloadducts 20 with acetic anhydride and activated zinc in
toluene at 85 °C under mechanical stirring, following Huet
conditions,15 afforded, after 72 h of reaction, the diastereomeric
cyclobutenes 17 and 18 in a ratio 81:19 and 59% yield, along
with the dichlorocycloadduct 22 (23%). Similarly, when the
mixture of adducts 20 was treated with activated Zn in refluxing
80% EtOH for 7 h, it afforded 17 and 18 in 69% yield and
recovered 22 (25%). Attempts to drive the process to completion
by increasing the reaction temperature or carrying out the
reaction under pressure in a sealed vessel caused loss of yield,
presumably due to decomposition of the cyclobutene products.
It was finally found that treatment of the mixture 20 with
activated Zn in 80% EtOH in a sealed vessel at 105 °C under
microwave irradiation (CEM Discover microwave reactor, IR
temperature monitoring) for 20 min delivered a mixture of 17
and 18 in 88:12 ratio and 79% yield.16 For synthetic purposes,
cyclobutene 17 was conveniently prepared by photochemical
reaction of 5 with (Z)-19 in acetonitrile, followed by Zn
dechlorination under microwave irradiation in 64% overall yield.
(11) Loutfy, R. O.; de Mayo, P. Can. J. Chem. 1972, 50, 3465–3471.
(12) Nelly, J. F. D.; Nelly, J. M.; McMurry, B. H. J. Chem. Soc., Perkin
Trans. 2 1999, 1933–1941.
(13) Shimo, T.; Somekawa, K.; Kuwakino, J.; Yemura, H.; Kumamoto, S.;
Tsuge, O.; Kanemasa, S. Chem. Lett. 1984, 1503–1504.
(14) (a) Warrener, R. N.; Pitt, I. G.; Rusell, R. A. Aust. J. Chem. 1992, 45,
1035–1044. (b) Pitt, I. G.; Russell, R. A.; Warrener, R. N. J. Am. Chem. Soc.
1985, 107, 7176–7178.
(15) (a) Gauvry, N.; Comoy, C.; Lescop, C.; Huet, F. Synthesis 1999, 574–
575. (b) Gauvry, N.; Lescop, C.; Huet, F. Eur. J. Org. Chem. 2006, 5207–5218.
(16) MicrowaVe in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2002; Chapters 2 and 4.
(17) For examples of directed hydroborations, see: (a) Evans, D. A.; Fu,
G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992, 114, 6671–6679. (b) Garrett,
C. E.; Fu, G. C. J. Org. Chem. 1998, 63, 1370–1371, and references therein.
FIGURE 3. Products 27-30 of the hydroboration-oxidation step and
relevant NOESY correlations.
J. Org. Chem. Vol. 73, No. 15, 2008 5947

Racamonde et al.
SCHEME 6
SCHEME 7
Incontrasttohydroboration,theoxymercuration-demercuration
of 26 proved to be highly regio- and stereoselective, leading
exclusively to the alcohol 29 in 92% yield. Since protection of
the secondary hydroxyl group was necessary for pursuing our
modified synthetic approach, we decided to investigate a
benzyloxymercuration-demercuration18 that would give rise
directly to the protected compound. Gratifyingly, treatment of
26 with mercuric acetate and benzyl alcohol in CH2Cl2 in the
presence of perchloric acid for 24 h, followed by demercuration
with alkaline sodium borohydride, afforded the benzyl derivative
31 as a single isomer in 86% yield (Scheme 6). It seems
reasonable to assume that the formation of 31 is a consequence
of selective coordination of Hg(OAc)2 to the basic groups of
the substrate guiding its addition to the endo face of the olefin,19
followed by anti, regioselective addition of the benzyl alcohol
at the less hindered carbon atom C-2′. Although the configu-
ration at C-1 in 31 is opposite to that in the target pheromone,
we knew from our previous work that the C-1 configuration
could be changed at a late stage of the route.3 Removal of the
acetonide protecting group of 31 under standard conditions (TFA
in MeOH/H2O) led to the pivotal intermediate 4.
Selective benzyl protection of the triol to the dibenzylate 32
was achieved using organotin chemistry in 82% overall yield
(Scheme 7). At this juncture, removing the secondary alcohol
of 32 by the Barton-McCombie procedure was targeted for
attention.20 Initial attempts to prepare the thiocarbonylimidazolyl
derivative by reaction of 32 with TCDI met with failure,
recovering only unreacted starting material. On the contrary,
sequential treatment of diol 32 with carbon disulfide and methyl
iodide in the presence of NaH resulted indeed in the clean
formation of the xanthate 33 in 92% yield, which when exposed
to the action of tri-n-butyltin hydride/AIBN in toluene at 100
°C afforded exclusively the ring-opened products 34, presumably
via ꢀ-radical elimination with release of ring strain to produce
a secondary radical which collapses with the hydride.21 Similar
radical ring-opening reactions on cyclobutylcarbinyl radicals
have already been reported,22 and it has been suggested that
the amount of ring-opening products increases at higher
temperature.23 As a consequence, the required reduction was
performed following Oshima’s procedure,24 by treating the
dithiocarbonate 33 with n-Bu3SnH and triethylborane in benzene
at room temperature. Under these conditions, the desired
deoxygenated derivative 35 was obtained in 78% yield from
diol 32, along with smaller amounts of open chain byproducts.
With 35 on hand, the final steps to the target compound were
conducted via well-established reactions. Hydrogenolysis (Pd/
C) of the benzyl ethers led in 83% yield to the triol 6, which
was oxidized with pyridinium chlorochromate25 in CH2Cl2 to
deliver directly the key intermediate 2 (79% yield), whose
enantiomeric purity was checked by chiral GC (Lipodex B). It
was previously described that reduction of the bicyclic keto
lactone (+)-2 with DIBAL-H, followed by acid-catalyzed
acetalization, furnished lineatin in 70-74% yield.2e We were
able to reproduce this transformation in 65% yield.26 The
spectral data and optical rotation of (+)-1 are in accordance
with those reported in the literature.2e
Conclusions
In summary, we have investigated thoroughly the photo-
chemical [2 + 2] cycloaddition of 2(5H)-furanone 5 to several
enol esters and ethers, 7a-c, ketene diethyl ketal, 12, and (Z)-
and (E)-1,2-dichloroethylene, (Z)- and (E)-19. In the reaction
with the unsymmetrical alkenes, the HT regioisomers predomi-
nate, indicating that the electronic effects are more important
than the steric effects in determining the regioselectivity of these
reactions. The photochemical cycloaddition to (Z)- and (E)-19
proceeded with high facial diastereoselectivity. Zn-Promoted
dechlorination under microwave irradiation gave the anti adduct
17 in good yield, which has been used as a precursor to
synthesize (+)-lineatin. This linear, 11-step synthesis has an
(18) Thaisrivongs, S.; Seebach, D. J. Am. Chem. Soc. 1983, 105, 7407–7413.
(19) (a) Henbest, H. B.; Nicholls, B. J. Chem. Soc. 1959, 227–236. (b)
Henbest, H. B.; McElhinney, R. S. J. Chem. Soc. 1959, 1834–1837. (c) Bratt,
K.; Garavelas, A.; Perlmutter, P.; Westman, G. J. Org. Chem. 1996, 61, 2109–
2117. (d) Paquette, L. A.; Bolin, D. G.; Stepanian, M.; Branan, B. M.;
Mallavadhani, U. V.; Tae, J.; Eisenberg, S. W. E.; Rogers, R. D. J. Am. Chem.
Soc. 1998, 120, 11603–11615. (e) Bernardelli, P.; Moradei, O. M.; Friedrich,
D.; Yang, J.; Gallou, F.; Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette,
L. A. J. Am. Chem. Soc. 2001, 123, 9021–9032.
(20) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1
1975, 1574–1585.
(24) (a) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29,
6125–6126. (b) Okano, K.; Ebata, T.; Koseki, K.; Kawakami, H.; Matsumoto,
K.; Matsushita, H. Chem. Pharm. Bull. 1993, 41, 861–865. (c) Moon, H. R.;
Kim, H. O.; Chun, M. W.; Jeong, L. S. J. Org. Chem. 1999, 64, 4733–4738.
(25) White, J. D.; Avery, M. A.; Carter, J. P. J. Am. Chem. Soc. 1982, 104,
5486–5489.
(21) For studies on cyclobutylcarbinyl radicals, see: (a) Shi, J.; Chong, S.-
S.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Org. Chem. 2008, 73, 974–982. (b) Maillard,
B.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1985, 443–450. (c) Beckwith,
A. L. J.; Moad, G. J. Chem. Soc., Perkin Trans. 2 1980, 1083–1092.
(22) Baldwin, J. E.; Burrell, R. C. J. Org. Chem. 2000, 65, 7139–7144.
(23) Castaing, M.; Pereyre, M.; Ratier, M.; Blum, P. M.; Davies, A. G.
J. Chem. Soc., Perkin Trans. 2 1979, 287–292.
(26) Due to the high volatility of lineatin, precaution must be taken when
solvents are evaporated.
5948 J. Org. Chem. Vol. 73, No. 15, 2008

Photochemical Cycloaddition of Disubstituted Olefins
2-one (8c exo), and (1R,4S,5R,7R)-7-tert-Butoxy-5-methyl-4-
pivaloyloxymethyl-3-oxabicyclo[3.2.0]heptan-2-one (10c endo).
A solution of 2(5H)-furanone 5 (130 mg, 0.61 mmol) and tert-
butylvinylether, 7c (0.80 mL, 6.1 mmol), in acetone (70 mL) was
irradiated through a Pyrex filter for 8 h. Evaporation of the solvent
and chromatography (hexane-EtOAc 6:1) gave a 29:22:19:12:9:
8:1 mixture of seven cycloadducts (118 mg, 0.38 mmol, 87% yield).
Repeated column chromatography (from hexane to hexane-EtOAc
9:1) provided the major components 8c endo (29%), 8c exo (22%),
and 10c endo (19%).
overall yield of 11% from lactone 5 and improves our previously
reported approach regarding simplicity with a comparable yield.
Experimental Section
General Methods: See the Supporting Information for details.
General Procedure for the Photochemical Reactions. Irradia-
tions were performed in a small conventional photochemical reactor
(two-necked vessel fitted with a Pyrex or quartz immersion-type
cooling jacket) using a high-pressure 125 W mercury lamp
(Cathodeon HPK-125). Methanol at -15 °C was used for refrigera-
tion of the immersion well jacket. The vessel was externally cooled
at -20 °C with a dry ice-CCl4 bath. The reaction mixture was
initially degassed by passage of oxygen-free argon through the
solution for 10 min and then irradiated under an atmosphere of
8c endo: Mp 100-102 °C (from EtOAc-pentane); IR (KBr)
2969, 2938, 1762, 1727, 1479, 1187, 1146 cm-1; MS (ESI+) 335
1
([M + Na]+, 100); H NMR (400 MHz, CDCl3) δ 5.16 (dd, J )
5.4, 3.8 Hz, 1H), 4.31 (dd, J ) 12.2, 3.8 Hz, 1H), 4.09 (dd, J )
12.2, 5.4 Hz, 1H), 3.87 (ddd, J ) 7.8, 6.3, 1.1 Hz, 1H), 2.78 (ddd,
J ) 12.9, 9.1, 7.8 Hz, 1H), 2.47 (ddd, J ) 9.1, 6.1, 1.1 Hz, 1H),
2.10 (ddd, J ) 12.9, 6.3, 6.1 Hz, 1H), 1.30 (s, 3H), 1.20 (s, 9H),
1.15 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 178.2, 178.0, 77.9,
74.0, 70.2, 63.4, 49.3, 39.5, 38.7, 33.5, 28.1, 27.1, 18.2.
1
argon. The progress of the reaction was monitored by GC or H
NMR analysis of aliquot samples.
(1R,4S,5R,6R)-6-Acetoxy-6-methyl-4-pivaloyloxymethyl-3-
oxabicyclo[3.2.0]heptan-2-one (8a exo) and (1R,4S,5R,6S)-6-
Acetoxy-6-methyl-4-pivaloyloxymethyl-3-oxabicyclo[3.2.0]heptan-
2-one (8a endo). A solution of 2(5H)-furanone 5 (150 mg, 0.71
mmol) and vinyl acetate, 7a (0.61 mL, 7.1 mmol), in acetone (70
mL) was irradiated through a Pyrex filter for 3 h. Evaporation of
the solvent and chromatography (hexane-EtOAc 5:1) afforded a
28:25:10:15:14:8 mixture of six cycloadducts (200 mg, 0.68 mmol,
95% yield). Repeated column chromatography (from hexane to
hexane-EtOAc 9:1) allowed us to isolate the major component
8a exo (28%) as a white solid and enriched fractions of 8a endo
(25%).
8c exo: Mp 70-72 °C (from EtOAc-pentane); IR (KBr) 2973,
2934, 1767, 1735, 1458, 1145 cm-1; MS (ESI+) 335 ([M + Na]+,
1
100); H NMR (400 MHz, CDCl3) δ 4.41 (dd, J ) 2.7, 2.3 Hz,
1H), 4.31 (dd, J ) 12.5, 2.7 Hz, 1H), 4.12 (dd, J ) 8.2, 7.3 Hz,
1H), 4.01 (dd, J ) 12.5, 2.3 Hz, 1H), 2.57 (ddd, J ) 9.9, 2.1, 1.0
Hz, 1H), 2.43 (ddd, J ) 11.8, 7.3, 2.1 Hz,1H), 2.33 (ddd, J )
11.8, 9.9, 8.2 Hz, 1H), 1.15 (s, 3H), 1.10 (s, 18H); 13C NMR (62.5
MHz, CDCl3) δ 179.3, 177.8, 82.4, 73.7, 69.6, 63.1, 51.0, 38.6,
38.4, 34.8, 28.4, 27.1, 11.1.
10c endo: Mp 93-95 °C (from EtOAc-pentane); [R]D +29.0
(c 0.39, CHCl3); IR (KBr) 2972, 2932, 1765, 1730, 1476, 1145
cm-1; MS (CI, NH3) 329 ([M + NH4]+, 99), 274 ([M + NH4 -
C4H9]+, 40), 257 ([M - C4H9O]+, 100); 1H NMR (400 MHz,
CDCl3) δ 4.38 (ddd, J ) 8.5, 7.6 Hz, 1H), 4.34 (dd, J ) 2.9, 2.1
Hz, 1H), 4.30 (dd, J ) 12.3, 2.9 Hz, 1H), 4.02 (dd, J ) 12.3, 2.1
Hz, 1H), 2.93 (ddd, J ) 7.6, 4.1, 0.9 Hz, 1H), 2.35 (ddd, J ) 12.1,
8.5, 4.1 Hz, 1H), 2.22 (dd, J ) 12.1, 8.5 Hz, 1H), 1.21 (s, 3H),
1.20 (s, 9H), 1.15 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 177.8,
174.5, 83.5, 74.6, 63.3, 62.3, 52.9, 43.1, 38.6, 36.3, 27.9, 27.1, 18.5.
Anal. Calcd for C17H28O5: C, 65.36; H, 9.03. Found: C, 65.15; H,
8.77.
8a exo: Mp 72-73 °C (from EtOAc-pentane); [R]D -32.2 (c
0.81, CHCl3); IR (KBr) 2982, 1781, 1739, 1466, 1175 cm-1; MS
1
(CI, NH3) 316 ([M + NH4]+, 100), 299 ([M + H]+, 5); H NMR
(400 MHz, CDCl3) δ 5.00 (t, J ) 8.2 Hz, 1H), 4.85 (dd, J ) 2.8,
1.9 Hz, 1H), 4.34 (dd, J ) 12.6, 2.8 Hz, 1H), 4.01 (dd, J ) 12.6,
1.9 Hz, 1H), 2.71 (dd, J ) 8.8, 2.9 Hz, 1H), 2.58 (ddd, J )12.3,
8.8, 8.2 Hz, 1H), 2.55 (ddd, J ) 12.3, 8.2, 2.9 Hz, 1H), 2.08 (s,
3H), 1.18 (s, 12H); 13C NMR (62.5 MHz, CDCl3) δ 178.1, 177.6,
170.7, 82.4, 72.2, 62.9, 50.2, 38.6, 38.6, 29.6, 27.1, 20.4, 10.7. Anal.
Calcd for C15H22O6: C, 60.39; H, 7.43. Found: C, 60.23; H, 7.48.
1
8a endo: H NMR (250 MHz, CDCl3) δ 4.81 (ddd, J ) 8.1,
(1R,4S,5S)- and (1S,4S,5R)-6,6-Diethoxy-5-methyl-4-pivaloy-
loxymethyl-3-oxabicyclo[3.2.0]heptan-2-one (13 and 14) and
(1S,4S,5S)- and (1R,4S,5R)-7,7-Diethoxy-5-methyl-4-pivaloy-
loxymethyl-3-oxabicyclo[3.2.0]heptan-2-one (15 and 16). A solu-
tion of lactone 5 (100 mg, 0.47 mmol) and 1,1-diethoxyethylene,
12 (0.31 mL, 2.35 mmol), in acetonitrile (70 mL) was irradiate
through a quartz filter for 35 min. Evaporation of the solvent and
column chromatography (hexane-EtOAc 12:1) afforded a 63:31:6
mixture of 13, 14, and 15/16 (132 mg, 0.40 mmol, 85% yield).
Repeated column chromatography (hexane-EtOAc 12:1) provided
enriched fractions of 13 and 14 which were analyzed. All attempts
to obtain enriched fractions of compounds 15 and 16 were
unsuccessful.
4.7, 1.7 Hz, 1H), 4.73 (t, J ) 3.8 Hz, 1H), 4.34 (dd, J ) 12.3, 3.8
Hz, 1H), 4.05 (dd, J ) 12.3, 3.8 Hz, 1H), 2.95 (ddd, J ) 14.0, 9.3,
8.1 Hz, 1H), 2.65 (ddd, J ) 9.3, 4.7, 1.7 Hz, 1H), 2.22 (dt, J )
14.0, 4.7 Hz, 1H), 2.10 (s, 3H), 1.36 (s, 3H), 1.15 (s, 9H); 13C
NMR (62.5 MHz, CDCl3) δ 177.7, 177.5, 170.4, 77.9, 73.5, 63.1,
47.8, 40.3, 38.7, 29.6, 27.0, 20.7, 17.7.
(1R,4S,5R,6S)-5-Methyl-6-pivaloyloxy-4-pivaloyloxymethyl-
3-oxabicyclo[3.2.0]heptan-2-one (8b endo). A solution of 2(5H)-
furanone 5 (100 mg, 0.47 mmol) and vinyl pivalate, 7b (0.5 mL,
4.7 mmol), in acetone (70 mL) was irradiated through a Pyrex filter
for8h.Evaporationofthesolventandchromatography(hexane-EtOAc
5:1) afforded a 44:13:12:11:11:5:4 mixture of seven cycloadducts
(131 mg, 0.38 mmol, 82% yield). Repeated column chromatography
(from hexane to hexane-EtOAc 9:1) allowed us to isolate the major
component 8b endo as a white solid: mp 60-61 °C (from
EtOAc-pentane); [R]D -7.8 (c 3.6, CHCl3); IR (KBr) 2975, 2937,
1776, 1764, 1735, 1481, 1145 cm-1; MS (CI, NH3) 357 ([M +
1
13: H NMR (500 MHz, CDCl3) δ 4.97 (dd, J ) 3.2 Hz, 1H),
4.38 (dd, J ) 12.3, 3.2 Hz, 1H), 4.04 (dd, J ) 12.3, 3.2 Hz, 1H),
3.20-3.55 (m, 4H), 2.49 (m, 3H), 1.30 (s, 3H), 1.20 (s, 9H,), 1.15
(m, 6H); 13C NMR (62.5 MHz, CDCl3) δ 178.5, 178.4, 103.4, 78.1,
63.5, 58.0, 57.6, 53.6, 38.7, 38.2, 34.3, 27.1, 14.9, 13.4; MS (CI +
NH3) 345 ([M + NH4]+, 100).
1
NH4]+, 100), 341 ([M + H]+, 5); H NMR (400 MHz, CDCl3) δ
4.77 (ddd, J ) 7.9, 4.1, 2.1 Hz, 1H), 4.62 (dd, J ) 3.7, 3.1 Hz,
1H), 4.35 (dd, J ) 12.5, 3.1 Hz, 1H), 4.04 (dd, J ) 12.5, 3.7 Hz,
1H), 2.96 (ddd, J ) 14.1, 9.2, 7.9 Hz, 1H), 2.67 (ddd, J ) 9.2, 4.1,
2.1 Hz, 1H), 2.19 (ddd, J ) 14.1, 4.1 Hz, 1H), 1.39 (s, 3H), 1.20
(s, 9H), 1.19 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 178.1, 177.8,
177.7, 78.0, 73.8, 63.3, 47.8, 40.6, 38.7, 38.6, 29.5, 27.1, 27.0, 17.5.
Anal. Calcd for C18H28O6: C, 63.51; H, 8.29. Found: C, 63.43; H,
8.50.
1
14: H NMR (500 MHz, CDCl3) δ 4.65 (dd, J ) 12.6, 7.6 Hz,
1H), 4.47 (dd, J ) 12.6, 2.3 Hz, 1H), 4.28 (dd, J ) 7.6, 2.3 Hz,
1H), 3.40 (m, 4H), 2.49 (m, 2H), 2.34 (dd, J ) 12.8, 9.8 Hz, 1H),
1.37 (s, 3H), 1.20 (s, 9H), 1.15 (m, 6H); 13C NMR (62.5 MHz,
CDCl3) δ 178.2, 177.9, 101.1, 84.8, 64.1, 58.2, 57.7, 54.7, 39.0,
38.7, 33.0, 27.1, 14.9, 16.5; MS (CI + NH3), 345 ([M + NH4]+,
100). Anal. Calcd for C17H28O6 (from a mixture of 13 and 14): C,
62.18; H, 8.59. Found: C, 62.19; H, 8.60.
(1R,4S,5R,6S)-6-tert-Butoxy-5-methyl-4-pivaloyloxymethyl-3-
oxabicyclo[3.2.0]heptan-2-one (8c endo), (1R,4S,5R,6R)-6-tert-
Butoxy-5-methyl-4-pivaloyloxymethyl-3-oxabicyclo[3.2.0]heptan-
(1S,4S,5S,6R,7R)-6,7-Dichloro-5-methyl-4-pivaloyloxymethyl-
3-oxabicyclo[3.2.0]heptan-2-one (21) and its Stereoisomers
J. Org. Chem. Vol. 73, No. 15, 2008 5949

Racamonde et al.
(1S,4S,5S,6S,7S)- (22), (1S,4S,5S,6R,7S)- (23), (1S,4S,5S,6S,7R)-
(24), and (1R,4S,5R,6R,7S)-6,7-Dichloro-5-methyl-4-pivaloy-
loxymethyl-3-oxabicyclo[3.2.0]heptan-2-one (25). A solution of
2(5H)-furanone 5 (600 mg, 2.8 mmol) and (Z)-1,2-dichloroethylene,
19 (1.1 mL, 14.1 mmol), in acetonitrile (280 mL) was irradiated
through a quartz filter for 7 h. Evaporation of the solvent and
chromatography (hexane-EtOAc 5:1) afforded a mixture of seven
dichlorocyclobutane stereoisomers (774 mg, 2.50 mmol, 89% yield)
in a ratio of 35:28:14:11:6:5:1. Repeated column chromatography
(from hexane-EtOAc 8:1 to hexane-EtOAc 3:1) provided analyti-
cal samples of 21-25.
reactor at 105 °C for 20 min. After cooling, the reaction mixture
was filtered through Celite. The solid was washed several times
with EtOH and EtOAc. Evaporation of the solvent gave a residue,
which was subjected to column chromatography (hexane-EtOAc
12:1) to afford the syn cycloadduct 18 (58 mg, 0.24 mmol, 9%
yield) ant the anti cycloadduct 17 (429 mg, 1.80 mmol, 64% yield).3
2-{(1R,4S)-4-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-4-methyl-
2-cyclobutenyl}-2-propanol (26). To a solution of 17 (900 mg,
4.83 mmol) in anhydrous THF (90 mL) at -78 °C was added,
dropwise, MeLi 1.6 M in ether (18.1 mL, 28.98 mmol), and the
mixture was stirred at -78 °C for 1 h and at room temperature for
2 h. Then, saturated solution of NH4Cl (40 mL) was slowly added,
the organic layer was separated, and the aqueous phase was
successively extracted with CH2Cl2 and EtOAc. The organic extracts
were washed with brine, dried, and the solvents removed to give a
crude which was dissolved in acetone (12 mL). To this solution
was added p-TsOH 0.05 M in acetone (0.6 mL, 0.03 mmol). After
being stirred for 12 h, the reaction mixture was diluted with CH2Cl2
and successively washed with a saturated aqueous solution of
NaHCO3 and brine before being dried and concentrated. The
product was purified by chromatography (hexane-EtOAc 4:1) to
give 26 (873 mg, 3.86 mmol, 80% yield) as a colorless oil.3
(1R,2S,3S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-(1-hydroxy-
1-methylethyl)-3 methylcyclobutanol (27) and Its Stereoiso-
mer (1R,2R,3R)- (29) and (1S,2R,3R)-2-[(4S)-2,2-Dimethyl-1,3-
d i o x o l a n - 4 - y l ] - 3 - ( 1 - h y d r o x y - 1 - m e t h y l e t h y l ) - 2 -
methylcyclobutanol (28) and Its Stereoisomer (1S,2S,3S)-30. To
a stirred solution of 1 M BH3-THF (0.45 mL, 0.45 mmol) in dry
THF (1 mL) at -15 °C was added dropwise a solution of 26 (50
mg, 0.22 mmol) in dry THF (1 mL). The mixture was stirred at
-15 °C for 7 h and quenched by careful addition of water. Then,
3 M NaOH (0.6 mL) and 30% H2O2 (0.36 mL) were successively
added, and the mixture was stirred for 15 h at room temperature.
The mixture was poured into brine containing 2% hydrochloric acid
(5 mL) and extracted with ethyl acetate. The organic layer was
washed with brine, dried, and evaporated to give a residue which
was purified by column chromatography (hexane-EtOAc 3:1) to
furnish 27 (10 mg, 0.04 mmol, 19% yield), 28 (7 mg, 0.03 mmol,
13% yield), 29 (18 mg, 0.07 mmol, 33% yield), and 30 (13 mg,
0.05 mmol, 24% yield) as colorless oils.
1
21: H NMR (500 MHz, CDCl3) δ 4.99 (t, J ) 4.1 Hz, 1H),
4.35 (dd, J ) 12.4, 4.1 Hz, 1H), 4.32 (m, 2H), 4.16 (dd, J ) 12.4,
4.1 Hz, 1H), 2.97 (dd, J ) 3.0 Hz, 1H), 1.5 (s, 3H), 1.20 (s, 9H);
1H NMR (500 MHz, C6D6) δ 4.56 (dd, J ) 5.0, 4.5 Hz, 1H), 4.02
(dd, J ) 12.1, 4.5 Hz, 1H), 3.83 (dd, J ) 12.1, 5.0 Hz, 1H), 3.77
(dd, J ) 5.6, 4.7 Hz, 1H), 3.72 (dd, J ) 5.6, 1.4 Hz, 1H), 2.51 (dd,
J ) 4.7, 1.4 Hz, 1H), 1.15 (s, 9H), 0.60 (s, 3H); 13C NMR (62.5
MHz, CDCl3) δ 177.5, 172.6, 79.0, 66.7, 62.4, 57.5, 52.7, 46.7,
38.7, 27.0, 19.5; MS (CI/NH3) 327 ([M + NH4]+, 66), 325 ([M +
NH4]+, 100), 256 ([M - 2Cl]+, 83); HRMS (FAB+) calcd for
[C13Cl2H18O4+H]+ 309.0660, found 309.0671. Anal. Calcd for
C13Cl2H18O4: C, 50.50; H, 5.87. Found: C, 50.17; H, 5.53.
22: Mp 128-129 °C (from pentane-EtOAc); [R]D +20.9 (c
1.05, CHCl3); IR (ATR) 2987, 2962, 1786, 1736, 1478, 1162 cm-1
;
1H NMR (500 MHz, CDCl3) δ 4.53 (dd, J ) 9.5, 8.2 Hz, 1H),
4.52 (dd, J ) 2.6, 1.7 Hz, 1H), 4.40 (dd, J ) 8.2, 1.0 Hz, 1H),
4.39 (dd, J ) 12.7, 2.6 Hz, 1H), 4.03 (dd, J ) 12.7, 1.7 Hz, 1H),
3.24 (dd, J ) 9.5, 1.0 Hz, 1H), 1.35 (s, 3H), 1.17 (s, 9H); 13C
NMR (62.5 MHz, CDCl3) δ 177.4, 171.2, 81.9, 65.2, 62.4, 55.9,
48.0, 47.1, 38.6, 27.1, 13.2; MS (CI/NH3) 327 ([M + NH4]+, 58),
325 ([M + NH4]+, 100), 256 ([M - 2Cl]+, 47). Anal. Calcd for
C13Cl2H18O4: C, 50.50; H, 5.87. Found: C, 50.46; H, 5.84.
1
23: H NMR (250 MHz, CDCl3) δ 5.03 (dd, J ) 8.3, 7.8 Hz,
1H), 4.99 (dd, J ) 3.5, 2.9 Hz, 1H), 4.60 (dd, J ) 7.8, 2.6 Hz,
1H), 4.40 (dd, J ) 12.5, 3.5 Hz, 1H), 4.12 (dd, J ) 12.5, 2.9 Hz,
1H), 3.24 (dd, J ) 8.3, 2.6 Hz, 1H), 1.45 (s, 3H), 1.17 (s, 9H); 13
C
NMR (62.5 MHz, CDCl3) δ 177.6, 171.5, 79.2, 64.9, 62.8, 52.0,
50.5, 47.4, 38.7, 27.1, 18.5; MS (CI/NH3) 327 ([M + NH4]+, 20),
325 ([M + NH4]+, 27), 256 ([M - 2Cl]+, 100); HRMS (FAB+)
calcd for [C13Cl2H18O4+H]+ 309.0660, found 309.0685.
27: [R]D -80.0 (c 0.05, CHCl3); IR (ATR) 3419 (br), 2969, 1455,
1
24: H NMR (500 MHz, CDCl3) δ 4.78 (dd, J ) 6.4, 1.5 Hz,
1
1157 cm-1; H NMR (500 MHz, CDCl3) δ 5.21 (t, J ) 6.5 Hz,
1H), 4.65 (dd, J ) 6.4, 1.0 Hz 1H), 4.53 (dd, J ) 2.8, 1.6 Hz, 1H),
4.37 (dd, J ) 12.7, 2.8 Hz, 1H), 4.03 (dd, J ) 12.7, 1.6 Hz, 1H),
3.08 (s, 1H), 1.50 (s, 3H), 1.15 (s, 9H); 13C NMR (62.5 MHz,
CDCl3) δ 177.4, 173.5, 82.1, 62.4, 59.7, 58.9, 51.1, 50.1, 38.6,
27.1 (CH3, (CH3)3C), 14.7 (CH3); MS (CI/ NH3) 325 ([M + NH4]+,
26), 256 ([M - 2Cl]+,100). Anal. Calcd for C13Cl2H18O4: C, 50.50;
H, 5.87. Found: C, 50.17; H, 5.53.
1H), 4.81 (d, J ) 3.5 Hz, 1H), 4.51 (m, 1H, H-1), 4.10 (dd, J )
8.4, 6.5 Hz, 1H), 3.98 (s, 1H), 3.78 (dd, J ) 8.4, 6.5 Hz, 1H), 2.02
(d, J ) 6.3 Hz, 1H), 1.81 (dd, J ) 12.6, 5.4 Hz, 1H), 1.56 (d, J )
12.6 Hz, 1H) 1.44 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 1.19 (s, 3H);
13C NMR (62.5 MHz, CDCl3) δ 109.6, 79.9, 73.7, 69.2, 65.5, 57.6,
44.4, 39.2, 29.1, 27.7, 26.1, 24.8, 22.2; MS (FAB+) 245 ([M +
H]+, 87), 227 ([M - OH]+, 100); HRMS (FAB+) calcd for
[C13H24O4+H]+ 245.1753, found 245.1766.
1
25: H NMR (500 MHz, CDCl3) δ 4.88 (dd, J ) 6.5, 1.4 Hz,
1H), 4.63 (d, J ) 6.5 Hz, 1H), 4.31 (m, 3H), 3.15 (s, 1H), 1.60 (s,
3H), 1.25 (s, 9H); 1H NMR (500 MHz, C6D6) δ 4.07 (dd, J ) 6.3,
1.3 Hz, 1H), 4.00 (dd, J ) 12.3, 6.9 Hz 1H), 3.99 (d, J ) 6.3 Hz,
1H), 3.96 (dd, J ) 12.3, 4.5 Hz, 1H), 3.53 (dd, J ) 6.9, 4.5 Hz,
1H), 2.40 (dd, J ) 1.3 Hz, 1H), 1.20 (s, 9H), 1.10 (s, 3H); 13C
NMR (62.5 MHz, CDCl3) δ 178.4, 173.4, 83.2, 61.2, 58.7, 55.2,
51.9, 51.0, 39.2, 27.5, 18.0; HRMS (FAB+) calcd for
[C13Cl2H18O4-Cl]+ 273.0894, found 273.0893.
28: [R]D -27.0 (c 0.15, CHCl3); IR (ATR) 3419 (br), 2969, 1455,
1
1157 cm-1; H NMR (500 MHz, CDCl3) δ 4.79 (t, J ) 6.8 Hz,
1H), 4.13 (dd, J ) 8.9, 6.8 Hz, 1H), 3.86 (s, 1H), 3.83 (dd, J )
8.9, 6.8 Hz, 1H), 3.77 (m, 1H), 2.19 (ddd, J ) 10.5, 7.9 Hz, 1H),
2.02 (ddd, J ) 12.0, 10.5, 8.7 Hz, 1H), 1.72 (s, 1H), 1.49 (dd, J )
12.0, 7.9 Hz, 1H), 1.44 (s, 3H), 1.35 (s, 3H), 1.28 (s, 3H), 1.18 (s,
3H), 1.05 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 107.7, 74.5,
70.9, 70.4, 66.8, 51.2, 47.6, 30.1, 29.4, 27.3, 26.0, 24.4, 20.8; MS
(FAB+) 245 ([M + H]+, 33), 227 ([M - OH]+, 100); HRMS
(FAB+) calcd for [C13H24O4+H]+ 245.1753, found 245.1754.
(1R,4S,5S)- and (1S,4S,5R)-5-Methyl-4-pivaloyloxymethyl-3-
oxabicyclo[3.2.0]hept-6-en-2-one (17 and 18). A solution of
2(5H)-furanone 5 (600 mg, 2.8 mmol) and (Z)-19 (1.1 mL, 14.1
mmol) in acetonitrile (280 mL) was irradiated using a high-pressure
125 W mercury lamp (Cathodeon HPK-125) for 7 h. Evaporation
of the solvent and column chromatography (hexane-EtOAc 3:1)
afforded a diastereomeric mixture of the dichlorocyclobutane
derivatives.
29: [R]D -53.0 (c 0.15, CHCl3); IR (ATR) 3419 (br), 2969, 1455,
1
1157 cm-1
; H NMR (500 MHz, CDCl3) δ 4.59 (t, J ) 7.0 Hz,
1H), 4.00 (dd, J ) 8.2, 7.0 Hz, 1H), 3.78 (m, 1H), 3.74 (dd, J )
8.2, 7.0 Hz, 1H), 3.41 (s, 1H), 2.32 (ddd, J ) 12.2, 9.3, 7.0 Hz,
1H), 2.23 (t, J ) 9.3 Hz, 1H), 1.80 (ddd, J ) 12.2, 9.3, 3.3 Hz,
1H), 1.43 (s, 3H), 1.34 (s, 3H), 1.25 (s, 3H), 1.11 (s, 3H), 1.08 (s,
3H); 13C NMR (62.5 MHz, CDCl3) δ 109.3, 76.8, 71.1, 69.1, 65.5,
51.7, 48.6, 29.7, 29.5, 27.4, 26.0, 24.7, 15.3; MS (FAB+) 245 ([M
The resulting crude was dissolved in (80%) aqueous EtOH (3.6
mL), and activated Zn dust (3.6 g, 55.0 mmol) was added. The
mixture was irradiated under pressure in a focused microwave
5950 J. Org. Chem. Vol. 73, No. 15, 2008

Photochemical Cycloaddition of Disubstituted Olefins
+ H]+, 10), 227 ([M - OH]+, 100); HRMS (FAB+) calcd for
[C13H24O4+H]+ 245.1753, found 245.1752.
allowed obtaining enriched fractions of the major product 34 which
was analyzed by NMR spectra.
34: 1H NMR (250 MHz, CDCl3) δ 7.35 (m, 10H), 5.50 (m, 1H),
4.74 (d, J ) 10.9 Hz, 1H), 4.52 (m, 2H), 4.48 (d, J ) 10.9 Hz,
1H), 4.08 (d, J ) 6.4 Hz, 2H), 3.95 (m, 1H), 2.58 (dd, J ) 13.8,
4.1 Hz, 1H), 2.20 (dd, J ) 13.8, 7.7 Hz, 1H), 1.80 (m, 1H), 1.72
(s, 1H), 1.60 (m, 1H), 1.20 (s, 6H); 13C NMR (62.5 MHz, CDCl3)
δ 137.6, 136.3, 128.6, 128.4, 128.1, 128.0, 127.7, 127.6, 124.8,
124.7, 76.0, 72.2, 70.7, 70.2, 66.4, 46.0, 44.2, 31.1, 28.3, 17.1.
2-[(1S,2S,4S)-4-(Benzyloxy)-2-[2-(benzyloxyethyl]-2-methyl-
cyclobutyl]-2-propanol (35). To a solution of diol 32 (154 mg,
0.40 mmol) in dry THF (7 mL) were added CS2 (253 µL, 4.2
mmol), in one portion, and NaH (60% in oil, 40 mg, 1.06 mmol)
under an Ar atmosphere, and the mixture was stirred for 2 h at
room temperature. Then, MeI (523 µL, 8.4 mmol) was added, and
the mixture was stirred at room temperature for 1 h. After
neutralization with AcOH, the solvent was removed to afford 33
(175 mg, 0.37 mmol, 92% yield) as a pale yellow solid. To a stirred
solution of the above xanthate in benzene (8 mL), Bu3SnH (293
µL, 1.09 mmol) and Et3B (1 M in hexane, 1.1 mL) were added
and the mixture was stirred for 2 h 30 min at room temperature.
Removal of the solvent afforded an oily residue, which was
subjected to column chromatography (hexane-EtOAc 4:1) to afford
35 (115 mg, 0.31 mmol, 78% yield from 32) as a colorless oil.
33: 1H NMR (250 MHz, CDCl3) δ 7.30 (m, 10H), 6.06 (dd, J )
5.2, 3.6 Hz, 1H), 4.52 (s, 2H), 4.44 (m, 2H), 4.08 (m, 1H), 3.83
(dd, J ) 11.1, 5.2 Hz, 1H), 3.73 (br s, 1H), 3.70 (dd, J ) 11.1, 3.6
Hz, 1H), 2.56 (s, 3H), 2.50 (dd, J ) 11.5, 7.3 Hz, 1H), 2.14 (d, J
) 9.1 Hz, 1H), 1.54 (dd, J ) 11.5, 8.2 Hz, 1H), 1.41 (s, 3H), 1.27
(s, 3H), 1.22 (s, 3H).
30: [R]D -3.7 (c 1.21, CHCl3); IR (ATR) 3419 (br), 2969, 1455,
1
1157 cm-1; H NMR (500 MHz, CDCl3) δ 4.41 (t, J ) 6.9 Hz,
1H), 4.25 (m, 1H), 3.97 (dd, J ) 8.2, 6.9 Hz, 1H), 3.70 (dd, J )
8.2, 6.9 Hz, 1H), 3.65 (s, 1H), 2.29 (s, 1H), 1.88 (dd, J ) 11.2, 7.5
Hz, 1H), 1.86 (d, J ) 8.6 Hz, 1H), 1.52 (dd, J ) 11.2, 8.1 Hz,
1H), 1.40 (s, 3H), 1.32 (s, 3H), 1.28 (s, 3H), 1.20 (s, 6H); 13C
NMR (62.5 MHz, CDCl3) δ 109.6, 78.4, 70.9, 66.0, 65.6, 64.0,
39.7, 36.4, 29.5, 27.5, 26.0, 24.7, 22.6; MS (FAB+) 245 ([M +
H]+, 39), 227 ([M - OH]+, 90), 169 (100), 154 (82); HRMS
(FAB+) calcd for [C13H24O4+H]+ 245.1753, found 245.1749.
2-{(1S,2S,4S)-4-(Benzyloxy)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-
4-yl]-2-methylcyclobutyl}-2-propanol (31). To a stirred solution
of 26 (78 mg, 0.34 mmol) in CH2Cl2 (1 mL) were added,
successively, benzyl alcohol (89 µL, 0.86 mmol), mercuric acetate
(135 mg, 0.43 mmol), and 70% perchloric acid (1 µL). The resulting
mixture was stirred at room temperature for 24 h. Then, the mixture
was added to cold CH2Cl2 (20 mL) and washed with cold H2O (10
mL), and the aqueous phase was extracted with CH2Cl2 (10 mL).
The combined organic phase was dried, filtered, and concentrated.
The resulting residue was dissolved in THF (3 mL) and added to
a vigorously stirred ice-cooled mixture of NaBH4 (13 mg, 0.34
mmol) in THF (3 mL) and aqueous pH 8 solution (3 mL). After
15 min, the reaction mixture was washed with water and the
aqueous phase was extracted with CH2Cl2. The combined organic
phase was dried, filtered, and concentrated. Column chromatography
of the resulting residue (from hexane-EtOAc 20:1 to hexane-EtOAc
12:1) afforded 31 (99 mg, 0.30 mmol, 86%) as a colorless oil.3
2-[1S,2S,4S)-4-(Benzyloxy)-2-[(1S)-2-(benzyloxy)-1-hydroxy-
ethyl]-2-methylcyclobutyl]-2-propanol (32). A suspension of triol
4 (191 mg, 0.65 mmol) and Bu2SnO (178 mg, 0.71 mmol) in MeOH
(4 mL) was heated at reflux until the solution became clear. The
solvent was evaporated to dryness to give a residue, which was
dissolved in dry toluene (4 mL). Then, tetrabutylammonium
bromide (209 mg) and benzyl bromide (85 µL, 0.71 mmol) were
added. The mixture was stirred for 24 h at the reflux temperature,
cooled to room temperature, and washed successively with a 10%
solution of Na2SO3 and brine. The organic layer was dried, and
the solvent was removed. The crude material was purified by
column chromatography (hexane-EtOAc 3:2) to afford diol 32 (205
mg, 0.53 mmol, 82% yield) as a colorless oil: [R]D +83.7 (c 0.45,
1
35: [R]D +97.2 (c 0.3, CHCl3); H NMR (250 MHz, CDCl3) δ
7.35 (m, 10H), 4.51 (s, 2H), 4.48 (m, 2H), 4.08 (m, 1H), 3.53 (m,
2H), 2.20 (dd, J ) 10.7, 7.2 Hz, 1H), 2.07 (d, J ) 9.0 Hz, 1H),
1.97 (m, 2H), 1.49 (dd, J ) 10.7, 8.1 Hz, 1H), 1.29 (s, 6H), 1.20
(s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 138.1, 136.1, 128.1, 128.0,
127.4, 127.3, 127.3, 127.2, 72.9, 71.2, 70.1, 70.1, 67.5, 62.9, 39.2,
35.5, 33.8, 29.7, 29.2, 28.3; HRMS (MALDI) calcd for
[C24H32O3+Na]+ 391.2244, found 391.2247.
(1S,2S,3S)-3-(2-Hydroxyethyl)-2-(1-hydroxy-1-methylethyl)-
3-methylcyclobutan-1-ol (6). A stirred solution of alcohol 35 (100
mg, 0.27 mmol) in a 30:1 mixture of EtOAc and HOAc (6 mL)
was hydrogenated over 10% Pd/C (309 mg) under a flow of H2 for
1 h. The catalyst was removed by filtration over Celite, and the
solvent was evaporated and the residue purified by column
chromatography (hexane-EtOAc 1:3) to afford 6 (41 mg, 0.21
mmol, 83% yield) as a colorless oil: [R]D +54.6 (c 0.61, CHCl3);
1H NMR (250 MHz, CDCl3) δ 4.28 (m, 1H), 3.69 (m, 2H), 2.26
(dd, J ) 10.9, 7.9 Hz, 1H), 1.87 (m, 2H), 1.81 (d, J ) 9.0 Hz,
1H), 1.44 (dd, J ) 10.9, 9.1 Hz, 1H), 1.28 (s, 3H), 1.25 (s, 3H),
1.19 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 71.5, 65.9, 64.1,
59.9, 41.7, 38.5, 33.3, 29.8, 29.4, 28.2; HRMS (CI+/CH4) calcd
for [C10H21O3-H2O]+ 171.1385, found 171.1386.
1
CHCl3); H NMR (250 MHz, CDCl3) δ 7.30 (m, 10H), 4.54 (m,
2H), 4.41 (m, 2H), 4.00 (m, 2H), 3.80 (br s, 1H), 3.52 (dd, J )
9.5, 2.5 Hz, 1H), 3.50 (br s, 1H), 3.44 (dd, J ) 9.5, 8.3 Hz, 1H),
2.05 (d, J ) 9.5 Hz, 1H), 1.99 (dd, J ) 11.1, 7.0 Hz, 1H), 1.45
(dd, J ) 11.1, 7.9 Hz, 1H), 1.32 (s, 3H), 1.24 (s, 3H), 1.17 (s, 3H);
13C NMR (62.5 MHz, CDCl3) δ 138.9, 138.1, 128.9, 128.8, 128.3,
128.2, 128.1, 128.0, 74.0, 73.9, 71.5, 71.0, 70.9, 70.8, 64.5, 38.6,
38.1, 30.0, 28.7, 24.3; HRMS (MALDI) calcd for [C24H32O4+Na]+
407.2193, found 407.2180.
(E)- or (Z)-(4S)-4,8-Dibenzyloxy-2,6-dimethyl-6-octen-2-ol
(34). To a stirred solution of diol 32 (40 mg, 0.10 mmol) in dry
THF (2 mL) were added CS2 (64 µL, 1.0 mmol) and NaH (60% in
oil, 11 mg, 0.26 mmol) under an Ar atmosphere. The mixture was
stirred at room temperature for 2 h. Then, MeI (130 µL, 2.5 mmol)
was added and the mixture was stirred for 1 h. After neutralization
with AcOH, the solvent was removed to afford 33 (45 mg, 0.095
mmol) as a pale yellow solid which was subjected to the following
reaction without further purification. To a heated (100 °C) solution
of tributyltin hydride (100 µL, 0.38 mmol) in dry toluene (0.7 mL)
was added a solution of azobisisobutyronitrile AIBN (5 mg, 0.03
mmol) in dry toluene (0.5 mL), and a solution of 33 in dry toluene
(2 mL) was added dropwise under an Ar atmosphere. The reaction
mixture was heated for 20 min. After cooling, the contents were
directly subjected to column chromatography (from hexane to
hexane-EtOAc 10:1) to furnish a mixture 1.3:1 of two products
(23 mg, 0.06 mmol, 66% yield). Repeated column chromatography
(1R,6S)-2,2,6-Trimethyl-3-oxabicyclo[4.2.0]octan-4,8-dione
(2). To a solution of triol 6 (50 mg, 0.26 mmol) in dry CH2Cl2 (5
mL) was added PCC (215 mg, 1.00 mmol). The mixture was stirred
for 4 h at room temperature, filtrated over Celite, and concentrated,
and the resulting residue was purified by column chromatography
(hexane-EtOAc 1:1) to give 2 (38 mg, 0.21 mmol, 79% yield) as
colorless crystals: mp 135-8 °C (from EtOAc-pentane); [R]D
+209.1 (c 0.93, acetone); 1H NMR (250 MHz, CDCl3) δ 2.95 (br
s, 1H,), 2.89 (m, 2H), 2.83 (d, J ) 16.8 Hz, 1H), 2.71 (d, J ) 16.8
Hz, 1H), 1.53 (s, 3H), 1.52 (s, 3H), 1.40 (s, 3H); 13C NMR (62.5
MHz, CDCl3) δ 205.6, 170.0, 80.5, 69.8, 58.0, 40.1, 29.5, 28.1,
26.9, 26.7.
(1R,4S,5R,7R)-3,3,7-Trimethyl-2,9-dioxatricyclo[3.3.1.04,7non-
ane (1). To a solution of 2 (28 mg, 0.15 mmol) in dry ether (1.5
mL) at -78 °C was added dropwise a 1.0 M solution of DIBAL-H
in hexane (0.36 mL, 0.36 mmol), and the mixture was stirred 30
min at -78 °C and 1.5 h at 0 °C. The reaction mixture was pored
J. Org. Chem. Vol. 73, No. 15, 2008 5951

Racamonde et al.
into ice-cold 10% aqueous tartaric acid (2 mL) and stirred for 20
min. The two layers were separated, and the organic extracts was
successively washed with saturated NaHCO3 and brine, dried, and
concentrated by distillation through a Vigreux column under
atmospheric pressure to give 1 (14 mg, 0.08 mmol, 65% yield):
Acknowledgment. We acknowledge financial support from
DGI(ProjectCTQ2004-2539)andCIRIT(Project2001SGR00178)
and grant from DGR to M.R.
Supporting Information Available: General experimental
1
[R]D +81.1 (c 0.46, CDCl3); H NMR (250 MHz, CDCl3) δ 5.08
1
procedures, full assignment of H and 13C NMR spectra, and
(d, J1 ) 3.2 Hz, 1H), 4.49 (t, J ) 3.9 Hz, 1H), 2.10 (ddd, J )
12.6, 3.2 Hz, 1H), 1.95 (dd, J ) 12.6, 2.1 Hz, 1H), 1.90 (d, J )
3.9 Hz, 1H), 1.73 (dt, J ) 10.0, 3.9 Hz, 1H), 1.65 (d, J ) 10.0 Hz,
1H), 1.23 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); 13C NMR (62.5 MHz,
CDCl3) δ 93.2, 71.9, 66.2, 48.5, 43.8, 42.5, 38.7, 29.3, 28.2, 26.7.
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO800970U
5952 J. Org. Chem. Vol. 73, No. 15, 2008