Intramolecular photochemical dioxenone - alkene [2 + 2] cycloadditions as an approach to the bicyclo[2.1.1]hexane moiety of solanoeclepin A

Article abstract of DOI:10.1021/jo0056500

A synthesis of the bicyclo[2.1.1]hexane substructure of solanoeclepin A(1), the most active natural hatching agent of potato cyst nematodes, was approached via an intramolecular [2 + 2] photocycloaddition. Aldehyde 12 containing the dioxenone chromophore served as a useful starting material, allowing the synthesis of a variety of photocycloaddition substrates via Grignard addition or via a Nozaki-Hiyama-Kishi reaction. Photelysis of the unsubstituted alkene 14 led to the expected crossed cycloadduct bicyclo[2.1.1]hexane 15 according to the so-called rule of five. However, several functionalized alkenes 18, 20, and 31 exhibited a complete reversal of cycloaddition regioselectivity, providing straight cycloadducts bicyclo[2.2.0]hexanes 21-26 and 4, respectively. Their structures were proved by a combination of extensive NMR measurements, X-ray analyses, and subsequent retro-aldol reactions. The latter de Mayo process allowed the formation of spiro-[3.5]nonane 35 and spiro[3.4]octane 36 as well as the cyclobutanes 37 and 38. Finally, the cyclization of the more rigid lactone precursor 28 occurred in high yield in the desired fashion with complete regio- and stereoselectivity to give 3 containing the core bicyclo[2.1.1]hexane skeleton of the natural product.

Full text of DOI:10.1021/jo0056500

J . Org. Chem. 2001, 66, 233-242
233
In tr a m olecu la r P h otoch em ica l Dioxen on e-Alk en e [2 + 2]
Cycloa d d ition s a s a n Ap p r oa ch to th e Bicyclo[2.1.1]h exa n e Moiety
of Sola n oeclep in A
Richard H. Blaauw, J ean-Franc¸ois Brie`re, Remco de J ong, J org C. J . Benningshof,
Angeline E. van Ginkel, J an Fraanje,† Kees Goubitz,† Henk Schenk,†
Floris P. J . T. Rutjes, and Henk Hiemstra*
Institute of Molecular Chemistry, Laboratories of Organic Chemistry and Crystallography, University of
Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
henkh@org.chem.uva.nl
Received September 18, 2000
A synthesis of the bicyclo[2.1.1]hexane substructure of solanoeclepin A (1), the most active natural
hatching agent of potato cyst nematodes, was approached via an intramolecular [2 + 2]
photocycloaddition. Aldehyde 12 containing the dioxenone chromophore served as a useful starting
material, allowing the synthesis of a variety of photocycloaddition substrates via Grignard addition
or via a Nozaki-Hiyama-Kishi reaction. Photolysis of the unsubstituted alkene 14 led to the
expected crossed cycloadduct bicyclo[2.1.1]hexane 15 according to the so-called rule of five. However,
several functionalized alkenes 18, 20, and 31 exhibited a complete reversal of cycloaddition
regioselectivity, providing straight cycloadducts bicyclo[2.2.0]hexanes 21-26 and 4, respectively.
Their structures were proved by a combination of extensive NMR measurements, X-ray analyses,
and subsequent retro-aldol reactions. The latter de Mayo process allowed the formation of spiro-
[3.5]nonane 35 and spiro[3.4]octane 36 as well as the cyclobutanes 37 and 38. Finally, the cyclization
of the more rigid lactone precursor 28 occurred in high yield in the desired fashion with complete
regio- and stereoselectivity to give 3 containing the core bicyclo[2.1.1]hexane skeleton of the natural
product.
Sch em e 1
In tr od u ction
Solanoeclepin A (1, Scheme 1), excreted in minute
quantities by the potato root, is the most active natural
hatching agent of the potato cyst nematode,1 organisms
causing severe crop losses in potato production. Its
structure was elucidated in 1992 after the joint efforts
of a number of research teams in The Netherlands.2 The
molecule contains all ring sizes ranging from three to
seven, including a highly strained bicyclo[2.1.1]hexanone
unit, which to the best of our knowledge is an unprec-
edented structural feature in natural products. The
fascinating architecture of this novel natural product,
combined with its scarcity and its potential role in the
search for an environmentally benign method to combat
the nematode, make it a challenging target for total
synthesis.
Sch em e 2
During our first studies toward this goal,3 the key step
of our approach toward the right-hand side substructure
of solanoeclepin A was based on a [2 + 2] photocyclo-
addition reaction (Scheme 2). We have recently reported3a
the successful diastereoselective formation and further
transformation of the highly substituted cyclobutane ring
3 starting from the lactone dioxenone precursor 2a .
Nevertheless, the cyclization process turned out to be
remarkably dependent on the substitution pattern of the
pendant alkenes of 2, leading either to bicyclo[2.1.1]-
hexanes of type 3 (crossed adducts) or bicyclo[2.2.0]-
hexanes (straight adducts), e.g., 4.
* Corresponding author.
† Laboratory of Crystallography.
(1) Mulder, J . G.; Diepenhorst, P.; Plieger, P.; Bru¨ggemann-Rotgans,
I. E. M. PCT Int. Appl. WO 93/02,083; Chem Abstr. 1993, 118, 185844z.
(2) Schenk, H.; Driessen, R. A. J .; De Gelder, R.; Goubitz, K.;
Nieboer, H.; Bru¨ggemans-Rotgans, I. E. M.; Diepenhorst, P. Croat.
Chem. Acta 1999, 72, 593.
(3) (a) Blaauw, R. H.; Brie`re, J .-F.; de J ong, R.; Benningshof, J . C.
J .; van Ginkel, A. E.; Rutjes, F. P. J . T.; Fraanje, J .; Goubitz, K.;
Schenk, H.; Hiemstra, H. J . Chem. Soc., Chem. Commun. 2000, 1463.
(b) Benningshof, J . C. J .; Blaauw, R. H.; van Ginkel, A. E.; Rutjes, F.
P. J . T.; Fraanje, J .; Goubitz, K.; Schenk, H.; Hiemstra H. J . Chem.
Soc., Chem. Commun. 2000, 1465.
Indeed, the dioxenone structure has been frequently
shown to be a versatile and efficient building block in
10.1021/jo0056500 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/08/2000

234 J . Org. Chem., Vol. 66, No. 1, 2001
Blaauw et al.
Sch em e 3
Sch em e 4a
synthetic photochemistry,4 especially allowing elegant
cyclobutane ring formation via [2 + 2] cycloaddition.
Moreover, in its intramolecular version, a high degree of
stereo- and regiochemical control is usually attainable
due to geometric contraints.5 For instance, the photo-
cyclization of 1,3-dioxen-4-one 5 bearing a 3-butenyl side
chain at C-5 gives crossed adduct 6 (Scheme 3), as
reported by Kaneko and Sato.6a This outcome follows the
so-called empirical rule of five,7 which explains the
regiochemistry by the supposedly preferential 1,5-closure
during the first step of the cyclization process. As far as
we know, this is the only example of a bicyclo[2.1.1]-
hexane prepared by this method. The behavior of more
highly substituted alkenes in this intramolecular process
with the alkene tethered at the dioxenone C-5 carbon has
not been studied to the best of our knowledge.8 However,
the substitution pattern of the alkene moiety is known
to govern the regioselectivity in the corresponding enone
series.5
a
Reaction conditions: (a) 4-bromo-1-butene, KOtBu, NaI (cat),
THF, 0 °C f reflux, 16 h; (b) Ac2O, acetone, -10 °C f rt, 16 h; (c)
hν, MeCN/acetone (9:1 v/v), rt, 3-4 h; (d) LiAlH4, rt, THG, 10 min.
Sch em e 5a
In conjunction with our previous work3a toward the
synthesis of the bicyclo[2.1.1]hexane substructure of
solanoeclepin A, we now report in detail our investiga-
tions of intramolecular photochemical [2 + 2] cycloaddi-
tions of several dioxenones of type 2. Subsequently, we
will outline the exploration of further chemistry of the
strained bicyclohexanes obtained, including their frag-
mentation via retro-aldol reactions in the so-called de
Mayo process.
a
Reaction conditions: (a) allyl bromide, KOtBu, NaI (cat), THF,
0 °C f reflux, 16 h; (b) Ac2O, acetone, -10 °C f rt, 16 h; (c) OsO4,
H2O/THF, rt, 8 h; (d) vinylmagnesium bromide, THF, -78 °C, 15
i
min; (e) MOMCl, Pr2NEtCH2Cl2, rt, 16 h; (f) hν, MeCN/aceton
(9:1 v/v), rt, 3-4 h; (g) LiAlH4, THF, rt 10 min.
Resu lts a n d Discu ssion
after about 4 h, and the expected 1,5-closure or crossed
adduct 9 was formed. This cycloadduct appeared to be
unstable, decomposing slowly under the reaction condi-
tions and during the subsequent workup. Therefore,
dioxanone 9 should be immediately reduced to diol 10.
However, the required conversion of this type of diox-
anone fused with a cyclobutane ring into a 1,3-diol proved
to be rather problematic. Reductions with either DIBALH
or LiAlH4 at temperatures ranging from -78 to 0 °C gave
poor yields. We reasoned that a more rapid and exhaus-
tive reduction was needed to circumvent these problems,
which were probably resulting from a competitive retro-
aldol process of the intermediate in the reduction process.
Gratifyingly, reaction with excess LiAlH4 at room tem-
perature was reasonably successful and gave diol 10 as
a crystalline compound in 47% overall yield from 8.
Importantly, the X-ray crystal structure determination
of 10 provided unequivocal proof of the bicyclo[2.1.1]-
hexane structure.
In itia l Stu d ies. Our first experiments had two objec-
tives, viz. (1) to verify the robustness of the photocycliza-
tion process of Kaneko6a and (2) to establish that further
transformations of the cycloadducts were possible without
destruction of the fragile bicyclo[2.1.1]hexane rings.6b Our
first photocyclization precursor was synthesized (Scheme
4) from commercially available tert-butyl acetoacetate 7
via alkylation with 4-bromo-1-butene and subsequent
dioxenone formation according to a literature procedure
leading to 8.9 On subjection of dioxenone 8 to irradiation
at 300 nm (acetonitrile/acetone 9:1 v/v, rt), complete
conversion of starting material was observed (1H NMR)
(4) Some examples of intramolecular [2 + 2] cycloadditions of
dioxenones and their applications: (a) Kaneko, C.; Sato, M.; Sakaki,
J .; Abe, Y. J . Heterocycl. Chem. 1990, 27, 25. (b) Winkler, J . D.; Mazur
Bowen, C.; Liotta, F. Chem. Rev. 1995, 95, 2003. (c) Haddad, N.;
Rukhman, I.; Abramovich, Z. J . Org. Chem. 1997, 62, 7629. (d) Winkler,
J . D.; Doherty, E. M. J . Am. Chem. Soc. 1999, 121, 7425.
(5) (a) Baldwin, S. W. Org. Photochem. 1981, 5, 123. (b) Crimmins,
M. T.; Reinhold, T. L. Org. React. 1993, 44, 297.
(6) (a) Sato, M.; Abe, Y.; Takayama, K.; Sekiguchi, K.; Kaneko, C.;
Inoue, N.; Furuya, T.; Inukai, N. J . Heterocycl. Chem. 1991, 28, 241.
(b) Sato, M.; Ohuchi H.; Abe Y.; Kaneko C. Tetrahedron: Asymmetry
1992, 3, 313.
(7) (a) Srinivasan, R.; Carlough, K. H. J . Am. Chem. Soc. 1967, 89,
4932. (b) Liu, R. S. H.; Hammond, G. S. J . Am. Chem. Soc. 1967, 89,
4936.
(8) Sato, M.; Abe, Y.; Ohuchi, H.; Kaneko C.; Inoue, N.; Furuya, T.;
Inukai, N. Heterocycles 1990, 31, 2115.
Having reached our first two objectives, we were
interested to see whether similar chemistry was possible
with a C-2 oxygen substituent in the 3-alkenyl side chain.
Therefore, the allyl derivative 11 was synthesized in the
same manner as 8 by reaction of keto-ester 7 with allyl
bromide10 (Scheme 5). The oxidative cleavage of olefin
11 by OsO4/NaIO4 allowed formation of the sufficiently
(9) (a) Sato, M.; Ogasawara, H.; Oi, K.; Kaneko, T. Chem. Pharm.
Bull. 1983, 31, 1896. (b) Huckin, S.; Weiler, L. J . Am. Chem. Soc. 1974,
96, 1082.
(10) Boyd, R. E.; Rasmussen, C. R.; Press, J . B. Synth. Commun.
1995, 25, 1045.

Dioxenone-Alkene [2 + 2] Cycloadditions
J . Org. Chem., Vol. 66, No. 1, 2001 235
Ta ble 1.
a
b
d
hν, MeCN/acetone. KOH, dioxane/H2O; CH2N2, MeOH. c Overall yield of the cyclization precusor from aldehyde 12. CrCl2, NiCl2
(cat)., DMF. e MOMCl, i-Pr2NEt, CH2Cl2. f Swern oxidation. (TMSOCH2)2, TMSOTf, CH2Cl2. Yield of the crude product. f Overall yield
from precursors 20a ,b. Structure of the main adduct drawn.
g
h
j
stable aldehyde 12, which served as a key intermediate
in our subsequent studies (vide infra). The reaction of
12 with vinylmagnesium bromide gave 13, thus allowing
the installation of the required secondary alcohol. The
alcohol was subsequently protected (14) with the meth-
oxymethyl group (MOM).
The photocycloaddition of 14 (Scheme 5) gave the
unstable crossed adduct 15 as a 50:50 diastereoisomeric
mixture. Immediate reduction as described above led to
diol 16 as a 50:50 mixture of isomers in 52% overall yield
from 14, thus establishing the feasibility of our synthetic
approach to the bicyclo[2.1.1]hexane substructure of
solanoeclepin A.
Expecting that this promising methodology could be
extended to prepare structures of type 3, our attention
was directed to more substituted alkenes for the in-
tramolecular photocycloaddition reaction. One additional
remark about the superfluous dioxenone C-6 methyl
group should be made here. The presence of this methyl
group greatly facilitates the synthesis of the required
dioxenones. We were aware, however, that removal of
this extra carbon at a later stage of the total synthesis
might not be a trivial chore.
In tr a m olecu la r [2+2] P h otocycloa d d ition w ith
Di- a n d Tr isu bstitu ted Alk en es. Aldehyde 12 served
as an excellent starting material for the preparation of
the photocycloaddition precursors collected in Table 1.
These syntheses began with a Nozaki-Hiyama-Kishi
reaction11 (NHK) of aldehyde 12 with suitable vinylic
bromides or cycloalkenyl triflates,12 followed by MOM
protection of the resulting alcohols 17 to give substrates
18. Alternatively, the intermediate alcohols were oxidized
(19) and subsequently converted into cyclic acetals13 20,
to prevent formation of mixtures of epimers at the
R-carbon atom of the secondary alcohol in the subsequent
photocycloaddition.
Upon irradiation of the substrates at 300 nm in an
acetone/acetonitrile mixture, smooth cyclization occurred
to afford cycloadducts 21-26 (Table 1). Surprisingly, all
of these photocycloadditions proceeded with complete
regioselectivity for 1,6-closure resulting in bicyclo[2.2.0]-
hexanes, which are the so-called straight adducts instead
of the expected crossed adducts. The structural proof of
the adducts was not trivial and will be outlined in the
sequel.
A readily noticed and most remarkable property of the
adducts 21-26 was their greatly enhanced stability
compared to bicyclo[2.1.1]hexanes 9 and 15. Silica gel
column chromatographic purification was possible and
allowed the full characterization of these strained mol-
(11) (a) Fu¨rstner, A. Chem. Rev. 1999, 99, 991. (b) Takai, K.;
Tagashira, M.; Kuroda, T.; Ishima, K.; Utimoto, K.; Nozaki, H. J . Am.
Chem. Soc. 1986, 108, 6048.
(12) Stang, P. J .; Hanack, M.; Subramania, L. R. Synthesis 1982,
95.
(13) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.

236 J . Org. Chem., Vol. 66, No. 1, 2001
Blaauw et al.
Sch em e 6a
ecules. Cycloalkenyl precursors 18a , 18b, 20a , and 20b
reacted more efficiently than the acyclic alkenes 18c and
18d . Ring size had no influence on the regiochemical
outcome as is apparent from comparison of the cyclohex-
enyl precursors with their cyclopentenyl analogues. The
MOM-protected precursors 18a and 18b led to diastereo-
isomeric mixtures with low selectivity (22) or unselec-
tively (21). Photocycloaddition of the acetals 20a and 20b
gave the corresponding straight adducts 23 and 24,
respectively, as single products in excellent yields. Both
acyclic alkene precursors 18c and 18d bearing a methyl
group led to the adducts 25 and 26, respectively, in
moderate yields, due to partial polymerization of the
precursors.14 Product 25 appeared to be a single diaste-
reoisomer as no other isomers in the 1H NMR of the crude
reaction mixture could be detected. NOE difference
measurements indicated the proximity of Ha and Hb and
of Hc and the proximate methyl group (Med) so that the
relative stereochemistry of 25 could be assigned. Pho-
tolysis of 18d proceeded more slowly than its analogue
18c and resulted in a complex mixture, of which three
inseparable diastereoisomers were obtained after column
chromatography in a ratio of 70:20:10. Due to the
presence of other minor adducts in the 1H NMR spectrum
of the crude product (minor adducts 26 <10%), which
turned out to be unstable during subsequent purification,
it was not possible so far to rule out the presence of small
amounts of crossed adducts. However, the determination
of the stereochemistry of the main isomer of 26 was
possible by using NOE difference experiments in the
same way as for 25. Both adducts 25 and 26 have the
protected alcohol group at the concave side and the
methyl group at the convex side of the bicyclo[2.2.0]-
hexane moiety. In both cases a noteworthy stereoselec-
tivity of the reaction was observed, probably due to the
more important steric interaction between the methyl
group with the MOM protected alcohol in comparison
with the methylene carbon in the cycloalkenyl structures.
a
Reaction conditions: (a) CrCl2, NiCl2 (cat), DMF, 50 °C, 7 h;
(b) hν, MeCN/acetone (9:1 v/v), rt, 2 h.
F igu r e 1. Chem 3D view of the crystal structure of 3.
Sch em e 7a
So far, di- and trisubstituted alkenes have thus ap-
peared reluctant to give 1,5-closure. We reasoned that
the regiochemistry could perhaps be directed by stereo-
electronic effects. Although not a general feature,15 it is
known that the [2 + 2] cycloaddition between an enone
and an alkene bearing an electron-withdrawing group
can be directed toward the formation of the cyclobutane
product with head to head regiochemistry. Then, the next
attempt to direct the regiochemical outcome of the [2 +
2] photocycloaddition was to use the more rigid lactone
28 (Scheme 6), which was obtained through spontaneous
cyclization of the product from the NHK reaction16 of
aldehyde 12 with triflate 27,17 bearing an additional
electron-withdrawing ester group. We were delighted to
find that the cyclization of this precursor did occur in a
1,5-fashion affording the desired crossed adduct 3 as a
single diastereoisomer in a clean reaction (according to
1H NMR) in 95% yield of unpurified crystalline product.
The adduct decomposed on a silica gel column, but could
a
Reaction conditions: (a) CrCl2, NiCl2 (cat), DMF, 50 °C, 18 h;
i
(b) MOMCl, Pr2NEt, CH2Cl2, rt, 16 h; (c) hν, MeCN/acetone (9:1
v/v), rt, 1 h.
be purified by recrystallization (mp 177-178 °C). An
X-ray crystal structure determination (Figure 1) proved
beyond doubt that the desired cycloaddition had taken
place. Comparison of the pentacyclic skeleton of 3 with
the target structure 1 indicates that in an efficient five-
step linear sequence from commercially available starting
materials a potentially useful intermediate for the total
synthesis of solanoeclepin A has been constructed.
To probe the generality of this cyclization mode, we
also investigated the five-membered ring ester 31 (Scheme
7). This precursor was constructed via an NHK reaction
of aldehyde 12 with triflate 29,18 followed again by MOM
protection. With this size ring, no spontaneous lacton-
ization of 30 was observed. Once again, the cyclization
(14) Piva-Le Blanc, S.; Pete, J .-P.; Piva, O. Chem. Commun. 1998,
235.
(15) General discussion and examples of stereoelectronic effects on
the regiochemical outcome of photocycloadditions of dioxenones and
enones with alkenes: (a) Fischer, E.; Gleiter, R. Angew. Chem., Int.
Ed. Engl. 1989, 28, 925. (b) Sato, M.; Abe, Y.; Ohuchi, H.; Kaneko C.;
Furuya, T.; Inukai, N. Heterocycles 1990, 31, 2115. (c) Andrew, D.;
Hastings, D. J .; Weedon, A. C. J . Am. Chem. Soc. 1994, 116, 10870.
(16) Knochel, P.; Rao, C. J . Tetrahedron 1993, 49, 29.
(18) J asperse, C. P.; Curran, D. P. J . Am. Chem. Soc. 1990, 112,
(17) Piers, E.; Tse, H. L. A. Can. J . Chem. 1993, 71, 983.
5601.

Dioxenone-Alkene [2 + 2] Cycloadditions
J . Org. Chem., Vol. 66, No. 1, 2001 237
Sch em e 8
F igu r e 2. Chem 3D view of the crystal structure of 4 (minor
isomer).
of 31 occurred exclusively with head to tail selectivity
affording the straight adduct 4 as a 60:40 mixture of
stereoisomers (78% yield) which was separable by flash
chromatography. The minor isomer was crystalline (mp
62-64 °C) and appeared suitable for a crystal structure
determination by X-ray diffraction. As shown in Figure
2 the strained tetracyclic structure is clearly the result
of 1,6-closure.
Mech a n ist ic Discu ssion . Thus, of the 10 photo-
cycloaddition precursors investigated, three (8, 14, and
28) cyclize in the expected crossed mode obeying the rule
of five, while the others (18a -d , 20a ,b, and 31) cyclize
in the unexpected straight mode. In view of the precedent
available,6a 8 and 14 show “normal” cyclization behavior
(rule of five). The mechanism of the photocycloaddition
reaction of alkenes with cyclic enones has been the
subject of a number of investigations.19 The most recent
experimental data on inter-20 and intramolecular pro-
cesses21 suggest that the regiochemistry of the cyclization
depends on the partitioning of the 1,4-biradical interme-
diate in the triplet excited state between cyclobutane ring
formation and bond cleavage to give the ground state
starting material as was first suggested several years ago
by Bauslaugh.22 About dioxenones much less is known.5
In the intramolecular process, the initial bond formation
should take place at the C(â) of the formed 1,4-biradical
dioxanyl moiety as has been shown by Winkler et al.23
Keeping this in mind, preliminary modeling studies by
molecular mechanics (MM2 force field)24 indicate that in
the case of cyclic alkenes 18a ,b, 20a ,b, and even with
the ester 31 initial five-membered ring formation cannot
be readily followed by a second CC-coupling due to
conformational constraints (the two radicals are almost
parallel). Therefore, the triplet 1,4-biradical intermediate
A (Scheme 8, the biradical derived from 31 is taken as
an example) would collapse back to ground state starting
material. However, if biradical structure B is formed
upon 1,6-closure, both radicals are properly oriented to
allow the second CC-bond formation to occur. On the
other hand, the more rigid lactone intermediate C puts
the two radicals in a favorable orientation (productlike
conformation by pyramidalization of the radical next to
the lactone), allowing facile crossed adduct formation. In
the case of acyclic alkenes 18c,d the conformational effect
is less obvious. Moreover, both low yields and slow
reaction rates indicate a difficult process. One can think
that the first attack on the least-hindered carbon of 18c
could justify the regiochemical outcome leading to the
straight adduct. Moreover, the presence of unstable side
products in the case of the analogue 18d , of which we
assume to be crossed adducts (see above), suggests that
the regioselectivity is less pronounced. However, during
the straight adduct formation, the second cyclization step
could be favored due to the lack of the methyl group
shielding the radical. At any rate, photochemistry once
again proves to be a very powerful synthetic technique,
producing in one step four contiguous quaternary carbon
centers with complete diastereocontrol.
(19) Schuster, D. I.; Lem, G.; Kaprinidis, N. K. Chem. Rev. 1993,
93, 3. (b) Crimmins, M. T.; Hauser, E. B. Org. Lett. 2000, 2, 281.
(20) Andrew, D.; Weedon, A. C. J . Am. Chem. Soc. 1995, 117, 5647.
(21) Rudolph, A.; Weedon, A. C. Can. J . Chem. 1990, 68, 1590.
(22) Bauslaugh, P. G. Synthesis 1970, 287.
(23) Winkler, J . D.; Shao, B. Tetrahedron Lett. 1993, 34, 3355.
(24) Audley, M.; Geraghty, N. W. A. Tetrahedron Lett. 1996, 37,
1641.
F u r th er Rea ction s of th e P h otoa d d u cts. We have
investigated the reduction and the fragmentation of a

238 J . Org. Chem., Vol. 66, No. 1, 2001
Blaauw et al.
Sch em e 9a
isomeric mixtures, which were fully characterized as
cyclobutanes by extensive NMR experiments. These
cyclobutane products can only arise from straight adducts
(a crossed adduct would lead to a five-membered ring),
so that herewith the 1,6-closure process in the case of
acyclic alkenes 18c and 18d was unequivocally proven.
Finally, this de Mayo variant provides a synthetic
pathway toward trifunctionalized spiro[3.5]nonanes or
spiro[3.4]octanes25 as well as to novel substituted cy-
clobutanes.
Con clu sion s
a
Reaction conditions: (a) LiAlH4, THF, rt, 5 min.
During our efforts toward the synthesis of solanoecl-
epin A, the construction of a variety of [2 + 2] cycload-
dition precursors has been efficiently achieved. The
unsubstituted olefins 8 and 14 gave the desired bicyclo-
[2.1.1]hexanes 9 and 15 according to the so-called rule
of five. However, photocyclization of the cyclic alkenes
18a ,b, 20a ,b, and 31 and the methyl-substituted acyclic
alkenes 18c,d exhibited remarkable regioselectivity for
1,6-closure, leading to highly substituted bicyclo[2.2.0]-
hexanes 21-26 and 4. Some of these cycloadducts were
subjected to a retro-aldol reaction under basic conditions
providing a straightforward way to polyfunctionalized
cyclobutanes (37 and 38), also contained within spiro
structures (35 and 36) with three or four new stereogenic
centers. Photocycloaddition of the more rigid lactone
precursor 28 proceeded with complete selectivity for the
1,5-mode of cyclization. This allowed the stereoselective
synthesis of the highly compact and complex pentacyclic
bislactone 3 in only five steps from commercially avail-
able tert-butyl acetoacetate. Reduction of this cycloadduct
afforded 32, which contains the appropriate substitution
pattern and stereochemistry for elaboration toward the
right-hand substructure of solanoeclepin A (1). Although
the exact effects which direct the regiochemical outcome
of the cycloadditions have to be further investigated, the
high regioselectivity of the cyclizations described above,
is noteworthy. This method provides an efficient and
stereoselective approach to densely functionalized bicyclo-
[2.1.1]hexanes and bicyclo[2.2.0]hexanes. Application of
this methodology in the total synthesis of solanoeclepin
A is currently under investigation. However, to facilitate
the formation of the eventual cyclobutanone functionality,
an analogue of 28 lacking the methyl at C-6 of the
dioxenone is now being studied. Details about these
investigations will follow in due course.
Sch em e 10a
a
Reaction conditions: (a) KOH, dioxane/H2O, rt, 150 min; (b)
CH2N2, MeOH, 0 °C.
number of the cycloadducts in order to obtain more
structural proof and to probe their potential synthetic
utility. First of all, cycloadduct 3 was reduced using LAH
at room temperature (Scheme 9), yielding a good
precursor3a (32) to construct the right-hand substructure
of solanoeclepin A. Interestingly, the complete reduction
of adduct 23 with LAH, as described above, proved to be
extremely efficient and provided diol 33 in virtually
quantitative yield.
It is well-known that a dioxanone fused to a cyclo-
butane can be readily fragmented via a retro-aldol
reaction, providing a variation on the classical de Mayo
approach. This process has found several applications in
the synthesis of complex molecules.4 The bicyclo[2.1.1]-
hexane 3 (Scheme 10) and bicyclo[2.2.0]hexanes 21-26
(Table 1) were subjected to the retro-aldol reaction under
basic conditions followed by methylation with diazo-
methane. Thereby, the crossed adduct 3 allowed forma-
tion of the interesting tricycloundecane structure 34 as
a single product. The pseudoequatorial position of the
ester group was deduced from the nuclear Overhauser
effect between the acetyl methyl group and the five-
membered ring protons.
New functionalized cyclobutane structures 35-38 were
obtained in good yields from the straight adducts. The
cyclohexane and cyclopentane straight adducts 23 and
24 underwent ring fragmentation to spiro compounds 35
and 36, respectively, obtained as mixtures of epimers in
ca. 75% overall yield from the alkene precursors 20a and
20b. Because the retro-aldol reaction proceeds through
an ester enolate intermediate, epimerization most prob-
ably takes place at this position. Both isomers of 35 could
be separated by flash chromatography. The main epimer
of 35 was a crystalline solid (mp 86 °C), which was
subjected to X-ray analysis. This epimer showed the same
stereochemistry as precursor 23. More importantly, this
X-ray structure ultimately proved the mode of photo-
cycloaddition, i.e., the structure of 23.
Exp er im en ta l Section
All reactions were carried out under an inert atmosphere
of dry nitrogen, unless stated otherwise. Standard syringe
techniques were applied for transfer of air-sensitive reagents
and dry solvents. Infrared (IR) spectra were obtained from
CHCl3 solutions and wavelengths (ν) are reported in cm-1. 1H
and 13C nuclear magnetic resonance (NMR) spectra were
determined in CDCl3 (400 and 100 MHz, respectively) unless
indicated otherwise. Chemical shifts (δ) are given in ppm
downfield from tetramethylsilane. Chromatographic purifica-
tion refers to flash chromatography26 using the indicated
solvent (mixture) and Acros silica gel (0.030-0.075 mm). Rf
values were obtained by using thin-layer chromatography
(TLC) on silica gel-coated plastic sheets (Merck silica gel F254
)
The retro-aldol sequence was also applied to the
straight adducts 25 and 26. Although the latter was not
completely pure, both underwent clean base-induced
fragmentation to 37 and 38, respectively, as 70:30
(25) (a) For a review, see: Sannigrahi M. Tetrahedron 1999, 55,
9007. (b) Pohmakotr, M.; Bunlaksananusorn, T.; Tuchinda, P. Tetra-
hedron Lett. 2000, 41, 377.
(26) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Dioxenone-Alkene [2 + 2] Cycloadditions
J . Org. Chem., Vol. 66, No. 1, 2001 239
with the solvent (mixture) mentioned before unless noted
otherwise. Melting points are uncorrected. Dry THF and Et2O
were distilled from sodium benzophenone ketyl prior to use.
Dry DMF, CH2Cl2, and MeCN were distilled from CaH2 and
stored over MS 4 Å under a dry nitrogen atmosphere. Tri-
ethylamine was dried and distilled from KOH pellets. All
commercially available reagents were used as received, unless
indicated otherwise.
temperature for 20 h. Saturated aqueous NH4Cl was added,
and the aqueous phase was extracted with EtOAc. The
combined organic layers were washed with water and brine,
dried over MgSO4, and concentrated in vacuo. Purification by
chromatography (EtOAc:PE ) 1:2) afforded 5-(2-cycloh ex-1-
en yl-2-h ydr oxyeth yl)-2,2,6-tr im eth yl-[1,3]dioxin -4-on e 17a
1
(402 mg, 86%) as a colorless oil. Rf ) 0.25. H NMR: 5.62 (br,
1H), 4.08-4.05 (m, 1H), 2.51 (dd, J ) 14.4, 5.1 Hz, 1H), 2.43
(dd, J ) 14.4, 7.7 Hz, 1H), 2.38 (br, 1H), 2.08-1.89 (m, 4H),
1.96 (s, 3H), 1.63-1.44 (m, 4H), 1.61 (s, 6H). 13C NMR: 164.5,
163.0, 139.4, 122.5, 104.7, 102.4, 75.4, 31.2, 24.9, 24.7, 24.5,
23.6, 22.3, 17.5. IR: 3600-3300, 1705, 1644. HRMS (FAB)
calculated for C15H23O4 (MH+) 267.1596, found 267.1598.
5-(2-Cyclop en t-1-en yl-2-h yd r oxyeth yl)-2,2,6-tr im eth yl-
[1,3]d ioxin -4-on e (17b). The reaction of aldehyde 12 (221 mg,
1.2 mmol) with cyclopentenyl triflate12 (510 mg, 2.4 mmol) at
room temperature for 20 h afforded 17b (193 mg, 64%) as a
colorless oil after purification (EtOAc:PE ) 1:4). Rf ) 0.13. 1H
NMR: 5.62 (br, 1H), 4.40 (br, 1H), 2.61 (dd, J ) 14.5, 4.4 Hz,
1H), 2.49 (dd, J ) 14.5, 8.2 Hz, 1H), 2.34-2.29 (m, 5H), 2.00
(s, 3H), 2.00-1.75 (m, 2H), 1.65 (s, 6H). IR: 3600-3300, 1714,
1644. HRMS (EI) calculated for C14H20O4 252.1362, found
252.1362.
5-Bu t-3-en yl-2,2,6-tr im eth yl[1,3]d ioxin -4-on e (8). To a
solution of 2-acetylhex-5-enoic acid tert-butyl ester9 (2.38 g,
11.2 mmol) and Ac2O (3.8 mL, 40 mmol) in acetone (1.8 mL)
was added, dropwise at -10 °C, concentrated H2SO4 (0.7 mL).
The solution was allowed to warm to room temperature over
16 h. The reaction mixture was poured into ice-water (150
mL) and subsequently stirred for 1 h. The aqueous phase was
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in
vacuo. Purification by chromatography (EtOAc:PE ) 1:6)
1
afforded 8 (1.25 g, 57%) as a colorless oil. Rf ) 0.25. H NMR:
5.80 (ddt, J ) 17.0, 10.2, 6.8, 1H), 5.06-4.96 (m, 2H), 2.38-
2.35 (m, 2H), 2.26-2.20 (m, 2H), 1.98 (s, 3H), 1.64 (s, 6H). IR:
1718, 1644.
5-Allyl-2,2,6-tr im eth yl-[1,3]d ioxin -4-on e (11). To a solu-
tion of 2-acetylpent-4-enoic acid tert-butyl ester10 (1.0 g, 5.0
mmol) and Ac2O (1.7 mL, 18 mmol) in acetone (0.8 mL) was
added, dropwise at -10 °C, concentrated H2SO4 (0.3 mL). The
solution was allowed to warm to room temperature over 16 h.
The reaction mixture was poured into ice-water (50 mL) and
subsequently stirred for 1 h. The aqueous phase was extracted
with CH2Cl2. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. Purifica-
tion by chromatography (EtOAc:PE ) 1:5) afforded 11 (575
mg, 63%) as a colorless oil. Rf ) 0.28. 1H NMR: 5.82 (ddt, J )
17.1, 10.1, 6.1 Hz, 1H), 5.07-5.00 (m, 2H), 3.02 (d, J ) 6.1
Hz, 2H), 1.97 (s, 3H), 1.66 (s, 6H). 13C NMR: 164.2, 161.8,
134.9, 114.9, 104.8, 102.8, 28.8, 24.9, 17.2. IR: 1710, 1644.
(2,2,6-Tr im et h yl-4-oxo-4H -[1,3]d ioxin -5-yl)a cet a ld e-
h yd e (12). To a solution of 11 (10.0 g, 55 mmol) in THF/water
(600 mL, 1:1 v/v) were added, at 0 °C, osmium tetraoxide (10
mL, 1 wt % solution in water, 0.4 mmol) and NaIO4 (28 g, 131
mmol). The resulting mixture was allowed to warm to room
temperature and stirred for 7 h. Then, most of the THF was
evaporated, and the remaining mixture was diluted with water
(500 mL) and extracted with EtOAc. The combined organic
layers were washed with 1 N NaHSO3, water, 2 N NaHCO3,
and brine, dried over MgSO4, and concentrated in vacuo.
Purification by chromatography (EtOAc:PE ) 1:1) afforded 12
5-(2-Hyd r oxy-3-m eth ylbu t-3-en yl)-2,2,6-tr im eth yl-[1,3]-
d ioxin -4-on e (17c). The reaction of aldehyde 12 (431 mg, 2.3
mmol) with 2-bromopropene (420 µL, 4.7 mmol) at room
temperature for 3 h afforded the product 17c (527 mg) as a
yellow oil. The crude product was used in the next reaction
without further purification. 1H NMR: 5.17 (br, 1H), 4.93 (br,
1H), 4.15 (dd, J ) 7.8, 4.4 Hz, 1H), 2.81-2.79 (br, 1H), 2.54
(dd, J ) 14.6, 4.4 Hz, 1H), 2.41 (dd, J ) 14.6, 7.7 Hz, 1H),
1.97 (s, 3H), 1.73 (s, 3H), 1.62 (s, 6H).
5-(2-H yd r oxy-(E)-p en t -3-en yl)-2,2,6-t r im et h yl-[1,3]d i-
oxin -4-on e (17d ). The reaction of aldehyde 12 (307 mg, 1.7
mmol) with (E)-1-bromo-1-propene (400 µL, 4.7 mmol) at room
temperature for 20 h afforded an inseparable mixture of
starting material 12 and desired alcohol 17d (1:9, 254 mg) as
a yellow oil. The crude product was used in the next reaction
without further purification. 1H NMR: 5.63 (dq, J ) 15.0, 6.4
Hz, 1H), 5.28 (ddq, J ) 15.2, 5.5, 1.5 Hz, 1H), 4.12-4.07 (m,
1H), 2.53 (dd, J ) 14.4, 5.2 Hz, 1H), 2.46 (dd, J ) 14.4, 6.9
Hz, 1H), 2.00 (s, 3H), 1.69 (dd, J ) 6.4, 1.5 Hz, 3H), 1.65 (s,
3H), 1.63 (s, 3H).
3-(2,2,6-Tr im et h yl-4-oxo-4H -[1,3]d ioxin -5-ylm et h yl)-
4,5,6,7-tetr a h yd r o-3H-isoben zofu r a n -1-on e (28). The reac-
tion of aldehyde 12 (300 mg, 1.6 mmol) with vinyl triflate 2717
(950 mg, 3.3 mmol) at 50 °C for 7 h afforded 28 (375 mg, 79%)
as a white powder after purification (EtOAc:PE ) 1:1). Rf )
1
(7.57 g, 75%) as a pale yellow semisolid. Rf ) 0.27. H NMR:
9.69 (s, 1H), 3.43 (s, 2H), 1.94 (s, 3H), 1.72 (s, 6H). 13C NMR
(in C6D6): 197.9, 165.72, 161.9, 106.0, 99.2, 40.6, 25.4, 17.7.
IR: 1722, 1650. HRMS (FAB) calculated for C9H13O4 (MH+)
185.0814, found 185.0809.
0.28. H NMR: 4.99 (br, 1H), 2.89 (dd, J ) 14.8, 3.8 Hz, 1H),
1
2.58 (dd, J ) 14.8, 6.4 Hz, 1H), 2.58-2.52 (m, 1H), 2.26-2.04
(m, 3H), 2.04 (s, 3H), 1.72-1.64 (m. 4H), 1.66 (s, 3H), 1.57 (s,
3H). 13C NMR: 172.9, 167.1, 163.7, 161.7, 126.8, 104.8, 98.6,
81.7, 27.9, 25.7, 23.4, 22.9, 21.2, 21.2, 19.8, 17.9. IR: 1748,
1706, 1639. HRMS (FAB) calculated for C16H21O5 (MH+)
293.1389, found 293.1395.
5-(2-Hyd r oxy-bu t-3-en yl)-2,2,6-tr im eth yl-[1,3]d ioxin -4-
on e (13). To a solution of aldehyde 12 (265 mg, 1.44 mmol) in
THF (1 mL) was added at -78 °C vinylmagnesium bromide
(1.5 mL, 1.0 M solution in THF, 1.5 mmol), and the resulting
solution was stirred at -78 °C for 15 min. Saturated aqueous
NH4Cl was added, and the resulting mixture was allowed to
warm to room temperature and diluted with EtOAc. The layers
were separated, and the aqueous phase was extracted with
EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to yield an
inseparable mixture of the desired alcohol 13 and starting
material 12 (60:40, 323 mg). The crude product was used in
the next reaction without further purification. 1H NMR: 5.93-
5.83 (ddd, J ) 17.1, 10.4, 5.8 Hz, 1H), 5.27 (dt, J ) 17.1, 1.5
Hz, 1H), 5.12 (dt, J ) 10.4, 1.4 Hz, 1H), 4.30 (m, 1H), 2.57
(dd, J ) 14.5, 4.9 Hz, 1H), 2.47 (dd, J ) 14.5, 7.4 Hz, 1H),
2.38 (br, 1H, OH), 2.01 (s, 3H), 1.66 (s, 3H), 1.65 (s, 3H).
Rep r esen ta tive P r oced u r e for th e Noza k i-Hiya m a -
Kish i Cou p lin g Rea ction s w ith Ald eh yd e 12. To a solution
of aldehyde 12 (325 mg, 1.76 mmol) in DMF (5 mL) at 0 °C
were added CrCl2 (1.08 g, 8.8 mmol), NiCl2 (2 mg, 0.02 mmol),
and cyclohexenyl triflate12 (1.2 g, 5.2 mmol). The mixture was
allowed to warm to room temperature and stirred at room
2-[1-Hyd r oxy-2-(2,2,6-tr im eth yl-4-oxo-4H-[1,3]d ioxin -5-
yl)eth yl)cyclop en t-1-en eca r boxylic Acid Meth yl Ester
(31). The reaction of aldehyde 12 (133 mg, 0.72 mmol) with
vinyl triflate 2918 (396 mg, 1.44 mmol) at 50 °C for 18 h
afforded 30 (164 mg, 73%) as a colorless oil after purification
(EtOAc:PE ) 1:2). Rf ) 0.29. 1H NMR: 4.84-4.77 (br, 1H),
4.34-4.32 (br, 1H), 3.74 (s, 3H), 2.80-2.71 (m, 2H), 2.70-2.55
(m, 4H), 2.10 (s, 3H), 1.89-1.81 (m, 2H), 1.67 (s, 3H), 1.66 (s,
3H).
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of th e
MOM P r otected P r od u cts. To a solution of alcohol 17a (215
mg, 0.81 mmol) and DIPEA (0.65 mL, 3.7 mmol) in CH2Cl2
(12 mL) at 0 °C was added MOMCl (170 µL, 2.3 mmol). The
mixture was stirred at 0 °C for 1 h and subsequently at room
temperature for 18 h. Saturated aqueous NH4Cl was added.
The layers were separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in
vacuo. Purification by chromatography (EtOAc:PE ) 1:3)
afforded 5-(2-Cycloh ex-1-en yl-2-m eth oxym eth oxyeth yl)-

240 J . Org. Chem., Vol. 66, No. 1, 2001
Blaauw et al.
2,2,6-tr im eth yl-[1,3]d ioxin -4-on e 18a (213 mg, 85%) as a
colorless oil. Rf ) 0.27. 1H NMR: 5.62 (br, 1H), 4.56 (d, J )
6.5 Hz, 1H), 4.45 (d, J ) 6.5 Hz, 1H), 4.05 (t, J ) 7.0 Hz, 1H),
3.31 (s, 3H), 2.56 (dd, J ) 14.2, 6.8 Hz, 1H), 2.49 (dd, J )
14.2, 7.2 Hz, 1H), 2.00-1.89 (m, 4H), 2.00 (s, 3H), 1.63-1.45
(m, 4H), 1.63 (s, 3H), 1.61 (s, 3H). 13C NMR: 164.5, 161.9,
136.2, 126.4, 104.6, 102.2, 93.6, 79.8, 55.4, 29.6, 25.0, 25.0, 24.8,
22.8, 22.5, 22.4, 17.8. IR: 1710, 1644. HRMS (EI) calculated
for C17H27O5 311.1858, found 311.1858.
5-(2-Meth oxym eth oxybu t-3-en yl)-2,2,6-tr im eth yl-[1,3]-
d ioxin -4-on e (14). The mixture of aldehyde 12 and alcohol
13 (2:3, 323 mg) afforded the MOM protected product 14 (157
mg, 43% from aldehyde 12) as a colorless oil and recovered
aldehyde 12 (58 mg, 22%) after purification (EtOAc:PE ) 1:2).
Rf ) 0.34. 1H NMR: 5.69 (ddd, J ) 17.6, 10.3, 7.6 Hz, 1H),
5.23-5.15 (m, 2H), 4.62 (d, J ) 6.6 Hz, 1H), 4.52 (d, J ) 6.6
Hz, 1H), 4.16 (q, J ) 6.7 Hz, 1H), 3.31 (s, 3H), 2.51 (d, J ) 6.7
Hz, 2H), 1.99 (s, 3H), 1.62 (s, 3H), 1.61 (s, 3H). 13C NMR:
165.0, 162.0, 137.8, 117.5, 104.7, 101.4, 94.0, 76.6, 55.3, 31.3,
25.1, 24.8, 17.8. IR: 1716, 1645. HRMS (EI) calculated for
°C f -50 °C, DMSO (166 µL, 2.34 mmol), then after 5 min a
solution of alcohol 17a (312 mg, 1.17 mmol) in CH2Cl2 (2 mL),
and finally, after 30 min triethylamine (0.74 mL, 5.3 mmol).
The mixture was stirred for 5 min and allowed to warm to
room temperature, and stirring was continued for 15 min.
Water was added, and the resulting mixture was stirred for
15 min. The layers were separated, and the aqueous phase
was extracted with CH2Cl2. The combined organic layers were
washed with saturated aqueous NH4Cl, saturated aqueous
NaHCO3, and brine, dried over MgSO4, and concentrated in
vacuo. Purification by chromatography (EtOAc:PE ) 1:4)
afforded 5-(2-Cycloh ex-1-en yl-2-oxoeth yl)-2,2,6-tr im eth yl-
[1,3]d ioxin -4-on e 19a (294 mg, 95%) as a colorless oil. Rf )
1
0.19. H NMR: 7.05 (br, 1H), 3.63 (s, 2H), 2.36-2.21 (m, 4H),
1.88 (s, 3H), 1.73 (s, 6H), 1.65-1.52 (m, 4H). 13C NMR: 197.0,
165.4, 162.2, 140.8, 138.6, 105.3, 100.3, 33.3, 26.1, 24.9, 23.1,
21.8, 21.4, 17.4. IR: 1709, 1651. HRMS (EI) calculated for
C
15H20O4 264.1362, found 264.1357.
5-(2-Cyclop en t-1-en yl-2-oxoeth yl)-2,2,6-tr im eth yl-[1,3]-
d ioxin -4-on e (19b). The oxidation of alcohol 17b (161 mg,
0.64 mmol) afforded ketone 19b (124 mg, 77%) as a colorless
oil after purification (EtOAc:PE ) 1:3). Rf ) 0.30. 1H NMR:
6.89 (br, 1H), 3.69 (s, 2H), 2.58-2.24 (m, 4H), 1.94-1.91 (m,
2H), 1.93 (s, 3H), 1.73 (s, 6H). 13C NMR: 194.5, 165.5, 162.1,
144.6, 144.4, 105.2, 99.9, 34.9, 33.9, 30.5, 24.7, 22.5, 17.6. IR:
1718, 1669.
C
13H20O5 256.1311, found 256.1304.
5-(2-Cyclop en t-1-en yl-2-m eth oxym eth oxyeth yl)-2,2,6-
tr im eth yl-[1,3]d ioxin -4-on e (18b). Alcohol 17b (131 mg,
0.52 mmol) afforded the MOM protected product 18b (102 mg,
66%) as a colorless oil after purification (EtOAc:PE ) 1:3). Rf
1
) 0.25. H NMR: 5.59 (br, 1H), 4.54 (d, J ) 6.5 Hz, 1H), 4.46
(d, J ) 6.5 Hz, 1H), 4.37 (t, J ) 6,9 Hz, 1H), 3.29 (s, 3H), 2.55
(dd, J ) 14.2, 7.0 Hz, 1H), 2.49 (dd, J ) 14.2, 7.0 Hz, 1H),
2.32-2.20 (m, 4H), 1.98 (s, 3H), 1.86-1.79 (m, 2H), 1.61 (s,
3H), 1.59 (s, 3H). 13C NMR: 164.7, 161.9, 143.3, 129.0, 104.6,
102.0, 94.0, 74.3, 55.4, 32.0, 30.3, 30.0, 25.1, 24.7, 23.2, 17.7.
IR: 1706, 1632. HRMS (EI) calculated for C16H24O5 296.1624,
found 296.1618.
5-(2-Met h oxym et h oxy-3-m et h ylb u t -3-en yl)-2,2,6-t r i-
m eth yl-[1,3]d ioxin -4-on e (18c). Alcohol 17c (527 mg, 2.3
mmol) afforded the MOM protected product 18c (437 mg, 69%
from aldehyde 12) as a colorless oil after purification (EtOAc:
PE ) 1:4). Rf ) 0.20. 1H NMR: 4.93 (br, 1H), 4.91 (br, 1H),
4.55 (d, J ) 6.5 Hz, 1H), 4.48 (d, J ) 6.5 Hz, 1H), 4.17-4.13
(m, 1H), 3.31 (s, 3H), 2.57 (dd, J ) 14.3, 6.1 Hz, 1H), 2.49 (dd,
J ) 14.3, 7.1 Hz, 1H), 2.01 (s, 3H), 1.72 (s, 3H), 1.64 (s, 3H),
1.62 (s, 3H). 13C NMR: 164.8, 161.9, 143.9, 114.0, 104.6, 101.8,
93.9, 79.1, 55.4, 29.9, 25.1, 24.8, 17.7, 16.8. IR: 1722, 1645.
HRMS (FAB) calculated for C14H23O5 (MH+) 271.1545, found
271.1543.
5-(2-Meth oxym eth oxy-(E)-p en t-3-en yl)-2,2,6-tr im eth yl-
[1,3]d ioxin -4-on e (18d ). The mixture of aldehyde 12 and
alcohol 17d (1:9, 254 mg) afforded the MOM protected product
18d (129 mg, 29% from aldehyde 12) as a colorless oil after
purification (EtOAc:PE ) 1:4). Rf ) 0.18.1H NMR: 5.65 (ddq,
J ) 15.2, 6.5, 0.5 Hz, 1H), 5.30 (ddq, J ) 15.2, 8.4, 1.6 Hz,
1H), 4.66 (d, J ) 6.6 Hz, 1H), 4.50 (d, J ) 6.6 Hz, 1H), 4.11
(semiq, 1H), 3.32 (s, 3H), 2.53 (dd, J ) 14.1, 7.0 Hz, 1H), 2.48
(dd, J ) 14.1, 6.9 Hz, 1H), 2.00 (s, 3H), 1.68 (dd, J ) 6.5, 1.6
Hz, 3H), 1.64 (s, 3H), 1.62 (s, 3H). 13C NMR: 164.7, 161.9,
130.7, 129.5, 104.6, 101.7, 93.4, 76.1, 55.2, 31.4, 25.0, 24.7, 17.7,
17.5. IR: 1722, 1647. HRMS (FAB) calculated for C14H23O5
(MH+) 271.1545, found 271.1550.
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of th e
Aceta l-P r otected P r od u cts 20a a n d 20b. To a solution of
ketone 19a (165 mg, 0.62 mmol) in CH2Cl2 (2 mL) at -78 °C
were added dropwise (TMSOCH2)2 (400 µL, 1.63 mmol) and
TMSOTf (44 µL, 0.24 mmol). The mixture was allowed to warm
to 0 °C over 1 h and kept at 0 °C for 30 h. Saturated aqueous
NaHCO3 was added, and the resulting mixture was stirred
for 15 min. The layers were separated, and the aqueous phase
was extracted with CH2Cl2. The combined organic layers were
washed with water and brine, dried over MgSO4, and concen-
trated in vacuo. Purification by chromatography (EtOAc:PE
) 1:4) afforded 5-(2-Cycloh ex-1-en yl-[1,3]d ioxola n -2-yl-
m eth yl)-2,2,6-tr im eth yl-[1,3]d ioxin -4-on e 20a (127 mg,
66%) as a colorless oil. Rf ) 0.24. 1H NMR: 5.77 (br, 1H), 3.84-
3.82 (m, 2H), 3.76-3.72 (m, 2H), 2.73 (s, 2H), 2.05-2.03 (m,
2H), 1.98 (s, 3H), 1.96-1.87 (m, 2H), 1.61 (s, 6H), 1.58-1.56
(m, 2H), 1.50-1.47 (m, 2H). 13C NMR: 165.5, 162.2, 136.5,
123.7, 111.0, 104.3, 100.9, 64.0, 31.6, 24.8, 24.7, 23.9, 22.5, 21.8,
18.2. IR: 1721, 1645. HRMS (FAB) calculated for C17H25O5
(MH+) 309.1702, found 309.1714.
5-(2-Cyclop en t-1-en yl-[1,3]d ioxola n -2-ylm eth yl)-2,2,6-
tr im eth yl-[1,3]d ioxin -4-on e (20b). Ketone 19b (79 mg, 0.32
mmol) afforded acetal 20b (61 mg, 66%) as a colorless oil after
purification (EtOAc:PE ) 1:6). Rf ) 0.13. 1H NMR: 5.71-5.69
(m, 1H), 3.93-3.90 (m, 2H), 3.87-3.82 (m, 2H), 2.82 (s, 2H),
2.43-2.39 (m, 2H), 2.33-2.27 (m, 2H), 2.01 (s, 3H), 1.93-1.85
(m, 2H), 1.55 (s, 6H). 13C NMR: 165.6, 162.2, 144.0, 127.9,
109.3, 104.2, 100.6, 64.2, 32.2, 31.6, 31.4, 24.7, 23.6, 18.1. IR:
1722, 1644.
Rep r esen ta tive P r oced u r e for th e In tr a m olecu la r [2
+ 2] Cycloa d d ition s. The photoreaction was carried out in
a Pyrex glass vessel with a Rayonet RPR 3000 Å at room
temperature. A solution of acetal 20a (127 mg, 0.41 mmol) in
acetonitrile/acetone (20 mL, 9:1 v/v) was degassed by bubbling
argon through for 30 min. The solution was kept under argon
and irradiated for 90 min. The reaction was followed by
monitoring the UV absorption of the starting material on TLC.
The solvent was removed in vacuo. Purification by chroma-
tography (EtOAc:PE ) 1:2) afforded adduct 23 (121 mg, 95%)
as a colorless oil. Rf ) 0.40. 1H NMR: 4.05-3.74 (m, 4H), 3.14
(d, J ) 14.8 Hz, 1H), 2.70 (dd, J ) 9.1, 6.7 Hz, 1H), 2.58 (d, J
) 14.1 Hz, 1H), 1.98-1.89 (m, 1H), 1.73-1.39 (m, 5H), 1.58
(s, 3H), 1.55 (s, 3H), 1.51 (s, 3H), 1.26-1.13 (m, 2H). 13C
NMR: 169.2, 108.1, 104.5, 77.4, 65.0, 64.4, 58.1, 41.7, 41.1,
36.7, 29.5, 29.2, 24.1, 21.1, 20.9, 20.3, 18.6. IR: 1730. HRMS
(FAB) calculated for C17H25O5 (MH+) 309.1702, found 309.1695.
4,4,6-Tr im e t h yl-3,5-d ioxa t r icyclo[5.2.1.01,6]d e ca n -2-
on e (9). Irradiation of a solution of 8 (50 mg, 0.26 mmol) in
acetonitrile/acetone (15 mL, 9:1 v/v) for 3.5 h afforded the
2-[1-Meth oxym eth oxy-2-(2,2,6-tr im eth yl-4-oxo-4H-[1,3]-
d ioxin -5-yl)eth yl]cyclop en t-1-en eca r boxylic Acid Meth yl
Ester (31). Alcohol 30 (117 mg, 0.38 mmol) afforded the MOM
protected product 31 (73 mg, 55%) as a colorless oil after
1
purification (EtOAc:PE ) 1:1). Rf ) 0.38. H NMR: 5.41 (t, J
) 14.2 Hz, 1H, H-9), 4.54 (s, 2H, CH3OCH2O), 3.71 (s, 3H,
C(O)OCH3), 3.34 (s, 3H, CH3OCH2O), 2.78-2.45 (m, 6H), 2.07
(s, 3H, H-7), 1.90-1.73 (m, 2H), 1.63 (s, 3H, CH3), 1.60 (s, 3H,
CH3). 13C NMR: 165.9 (C(O)OCH3), 165.3 (C-4), 161.9 (C-6),
157.4 (C-10), 130.9 (C-14), 104.7 (C-2), 101.0 (C-5), 95.4
(CH3OCH2O), 72.2 (C-9), 55.8 (CH3OCH2O), 51.2 (C(O)OCH3),
34.0, 33.1, 29.4, 25.4 (CH3), 24.6 (CH3), 21.6, 17.7 (C-7). IR:
1712, 1642. HRMS (FAB) calculated for C18H27O7 (MH+)
355.1757, found 355.1765.
Rep r esen ta tive P r oced u r e for th e Oxid a tion of th e
Alcoh ols 17a a n d 17b. To a solution of oxalyl chloride (113
µL, 1.28 mmol) in CH2Cl2 (4 mL) was added dropwise, at -60

Dioxenone-Alkene [2 + 2] Cycloadditions
J . Org. Chem., Vol. 66, No. 1, 2001 241
unstable cycloadduct 9 (50 mg, 100% crude yield) as a yellow
1.93 (d, J ) 13.2 Hz, 1H), 1.56 (s, 6H), 1.53 (s, 3H), 1.26 (s,
3H). 13C NMR: 168.9, 104.9, 95.7, 77.1, 74.9, 55.4, 50.1, 42.4,
39.6, 29.8, 29.3, 27.6, 23.0, 21.3. IR: 1729. HRMS (FAB)
calculated for C14H23O5 (MH+) 271.1545, found 271.1539.
3-Met h oxym et h oxy-5,6,8,8-t et r a m et h yl-7,9-d ioxa t r i-
cyclo[4.4.0.01,4]d eca n -10-on e (26). Irradiation of a solution
of alkene 18d (111 mg, 0.41 mmol) in acetonitrile/acetone (20
mL, 9:1 v/v) for 6.5 h afforded a mixture of straight adducts
(70:20:10) 26 (40 mg, 36%) as a colorless oil after purification
oil. The crude product was used immediately in the next
1
reaction without further purification. H NMR (C6D6): 2.56-
2.53 (m, 1H), 2.11-2.09 (m, 1H), 1.95-1.89 (m, 1H), 1.46-
1.37 (m, 1H), 1.41 (s, 3H), 1.32-1.15 (m, 2H), 1.30 (s, 3H), 1.03
(d, J ) 6.5 Hz, 1H), 0.88 (s, 3H). 13C NMR (C6D6): 169.8, 109.8,
83.9, 51.0, 46.2, 42.8, 30.9, 30.7, 25.5, 23.5.
8-Meth oxym eth oxy-4,4,6-tr im eth yl-3,5-d ioxa tr icyclo-
[5.2.1.01,6]d eca n -2-on e (15). Irradiation of a solution of 14
(157 mg, 0.61 mmol) in acetonitrile/acetone (20 mL, 9:1 v/v)
for 3 h afforded the unstable cycloadduct 15 (159 mg, 100%
crude yield) as yellow oil. The crude product was used
immediately in the next reaction without further purification.
1H NMR: 4.40 (d, J ) 6.9 Hz, 1H), 4.37 (d, J ) 6.9 Hz, 1H),
4.31 (s, 2H), 3.92 (dd, J ) 6.6, 1.6 Hz, 1H), 3.83-3.81 (m, 1H),
3.07 (s, 3H), 3.04 (s, 3H), 2.68-2.66 (m, 1H), 2.54-2.44 (m,
4H), 2.07 (dd, J ) 12.3, 1.7 Hz, 1H), 1.98 (d, J ) 6.6 Hz, 1H),
1.93 (ddd, J ) 12.3, 6.8, 2.9 Hz, 1H), 1.69-1.65 (m, 1H), 1.47
(s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H), 1.26 (s, 3H),
0.87 (d, J ) 6.9 Hz, 1H), 0.77 (s, 3H).
1
(EtOAc:PE ) 1:7). Rf ) 0.12. Ma in a d d u ct: H NMR (C6D6):
4.49 (ddd, J ) 9.6, 6.7, 4.3 Hz, 1H), 4.36 (d, J ) 6.5 Hz, 1H),
4.34 (d, J ) 6.5 Hz, 1H), 3.28 (ddd, J ) 13.1, 9.6, 2.5 Hz, 1H),
3.13 (s, 3H), 2.77 (dq, J ) 7.2, 4.7 Hz, 1H), 2.62 (ddd, J ) 6.8,
4.7, 2.5 Hz, 1H), 2.23 (dd, J ) 13.2, 6.9 Hz, 1H), 1.42 (s, 3H),
1.22 (s, 3H), 1.13 (s, 3H), 1.07 (d, J ) 7.2, 3H). IR: 1731. HRMS
(FAB) calculated for C14H23O5 (MH+) 271.1545, found 271.1552.
Cycloa d d u ct 3. Irradiation of a solution of alkene 28 (100
mg, 0.34 mmol) in acetonitrile/acetone (20 mL, 9:1 v/v) for 2 h
afforded 3 (95 mg, 95% crude yield), which was used in the
next reaction without further purification. X-ray crystal
structure determination was allowed after recrystallization
Cycloa d d u ct 21. Irradiation of a solution of 18a (145 mg,
0.47 mmol) in acetonitrile/acetone (25 mL, 9:1 v/v) for 30 min
afforded a 50:50 mixture of diastereomers 21a and 21b (120
mg, 83%) as colorless oil after purification (EtOAc:PE ) 1:2).
1
from CH2Cl2/pentane. Colorless crystals. mp 177-178 °C. H
NMR: 4.54 (d, J ) 4.2 Hz), 2.39 (dt, J ) 13.3, 4.7 Hz, 1H),
2.33 (dd, J ) 12.8, 4.2 Hz, 1H), 2.23-2.20 (m, 1H), 1.98 (d, J
) 12.8 Hz, 1H), 1.89-1.85 (m, 1H), 1.81-1.61 (m, 2H), 1.73
(s, 3H), 1.64 (s, 3H), 1.56-1.40 (m, 2H), 1.40 (s, 3H), 1.05-
0.93 (m, 1H). 13C NMR: 174.7, 164.9, 109.9, 83.2, 79.7, 62.1,
60.4, 51.5, 33.7, 31.1, 29.2, 21.8, 21.7, 21.4, 20.4, 19.4.
Cycloa d d u ct 4. Irradiation of a solution of 31 (61 mg, 0.17
mmol) in acetonitrile/acetone (11.1 mL, 9:1 v/v) for 60 min
afforded a 40:60 mixture of diastereomers 4a and 4b (47 mg,
78%) as colorless oil after purification (EtOAc:PE ) 1:1).
Repeated chromatography led to pure isomers. 4a : X-ray
crystal structure determination was allowed after recrystal-
lization from CH2Cl2/pentane. Colorless crystals. Rf ) 0.41. mp
62-64 °C. 1H NMR: 4.55 (d, J ) 0.6.6 Hz, 1H), 4.50-4.46 (m.
2H), 3.62 (s, 3H), 3.32 (s, 3H), 2.91 (dd, J ) 13.7, 9.9 Hz, 1H),
2.63-2.56 (m, 1H), 2.29 (dd, J ) 13.7, 4,5 Hz, 1H), 2.02-2.02
(m, 1H), 1.92 (s, 3H), 1.87-1.76 (m, 3H), 1.66-1.56 (m, 1H),
1.55 (s, 3H), 1.50 (s, 3H). 13C NMR: 174.2, 170.2, 104.3, 95.6,
77.9, 70.6, 65.0, 60.8, 55.4, 51.0, 40.5, 33.9, 32.8, 29.6, 29.1,
28.6, 24.2, 23.4. IR: 1724. 4b: colorless oil. Rf ) 0.34. 1H
NMR: 4.72 (t, J ) 6.6 Hz, 1H), 4.68 (d, J ) 6.6 Hz, 1H), 4.63
(d, J ) 6.6 Hz, 1H), 3.71 (s, 3H), 3.37 (s, 3H), 2.79 (dd, J )
13.2, 6.5 Hz, 1H), 2.58 (dd, J ) 13.1, 6.8 Hz, 1H), 2.55-2.52
(m, 1H), 2.11 (dd, J ) 12.4, 5.5 Hz, 1H), 1.77-1.44 (m, 4H),
1.60 (s, 3H), 1.55 (s, 3H), 1.44 (s, 3H). 13C NMR: 179.7, 173.1,
104.0, 95.4, 76.3, 70.3, 65.0, 62.5, 55.4, 51.5, 40.2, 32.5, 31.4,
29.3, 28.4, 26.9, 23.2, 22.5.
1
Rf ) 0.29 and Rf ) 0.26. H NMR: 4.64 (d, J ) 6.6 Hz, 1H),
4.59 (d, J ) 6.6 Hz, 1H), 4.57 (d, J ) 4.4 Hz, 1H), 4.55 (d, J )
4.4 Hz, 1H), 4.15 (t, J ) 6.4 Hz, 1H), 4.04 (dd, J ) 9.7, 6.6 Hz,
1H), 3.36 (s, 3H), 3.35 (s, 3H), 3.00 (dd, J ) 13.4, 9.7 Hz, 1H),
2.79 (dd, J ) 9.7, 4.5 Hz, 1H), 2.74 (dd, J ) 13.0, 6.5 Hz, 1H),
2.53 (dd, J ) 13.0, 6.4 Hz, 1H), 2.16 (t, J ) 7.4 Hz, 1H), 2.13
(dd, J ) 13.4, 6.6 Hz, 1H), 2.00-1.00 (m, 8H), 1.59 (s, 6H),
1.56 (s, 3H), 1.52 (s, 6H) 1.45 (s, 3H). 13C NMR: 169.8, 169.1,
104.8, 103.9, 78.6, 77.0, 76.0, 55.5, 52.3, 52.2, 49.8, 43.7, 42.5,
31.2, 29.5, 29.4, 29.1, 29.1, 28.4, 27.9, 24.7, 22.9, 21.6, 21.5,
20.9, 20.9, 20.8, 20.6, 18.4. IR: 1714. HRMS (EI) calculated
for C17H26O5 310.1780, found 310.1776.
Cycloa d d u ct 22. Irradiation of a solution of 18b (92 mg,
0.31 mmol) in acetonitrile/acetone (20 mL, 9:1 v/v) for 30 min
afforded a 43:57 mixture of diastereomers 22a and 22b (89
mg, 97%) as a colorless oil after purification (EtOAc:PE ) 1:2).
1
Rf ) 0.27 and Rf ) 0.22. H NMR: 4.65 (d, J ) 6.8 Hz, 1H),
4.60 (d, J ) 6.8 Hz, 1H), 4.59 (d, J ) 6.6 Hz, 1H), 4.55 (d, J )
6.6 Hz, 1H), 4.36 (dd, J ) 5.9, 5.9 Hz, 1H), 4.31 (dd, J ) 9.9,
5.9 Hz, 1H), 3.36 (s, 3H), 3.32 (s, 3H), 2.95 (dd, J ) 13.6, 9.9
Hz, 1H), 2.88 (d, J ) 9.0 Hz, 1H), 2.80 (dd, J ) 13.6, 5.1 Hz,
1H), 2.58 (dd, J ) 13.6, 6.3 Hz, 1H), 2.35 (d, J ) 9,0 Hz, 1H),
2.25 (dd, J ) 13.6, 5.9 Hz, 1H), 2.12-2.05 (m, 1H), 2.10 (dd, J
) 13.9, 6.8 Hz, 1H), 1.94 (dd, J ) 13.8, 5.7 Hz, 1H), 1.83-1.66
(m, 3H), 1.82-1.36 (m, 4H), 1.60 (s, 3H), 1.55 (s, 3H), 1.52 (s,
3H) 1.51 (s, 3H), 1.50-1.39 (m, 2H), 1.46 (s, 3H), 1.44 (s, 3H).
13C NMR: 170.1, 104.3, 103.9, 96.0, 95.3, 76.0, 74.5, 74.2, 62.2,
61.7, 55.6, 55.4, 54.2, 48.0, 42.6, 41.4, 31.6, 29.3, 29.2, 28.9,
28.6, 27.4, 26.4, 25.8, 25.3, 25.1, 24.9. IR: 1714.
Rep r esen ta tive P r oced u r e for th e Red u ction Rea c-
tion . To a solution of LiAlH4 (1 M in THF, 0.9 mL, 0.9 mmol)
was added dropwise at room temperature a solution of the
crude cycloadduct 9 (50 mg) in THF (0.5 mL). The reaction
mixture was stirred for 10 min. Then, the reaction was
quenched by addition of EtOAc, and saturated aqueous Na2-
SO4 (10 drops) was added. The resulting mixture was stirred
for 1 h. After addition of additional solid Na2SO4, the mixture
was filtered through Celite and concentrated in vacuo. Puri-
fication by chromatography (EtOAc:PE ) 3:1) afforded 1-h y-
d r oxym eth yl-5-m eth ylbicyclo[2.1.1]h exa n -5-ol 10 (17 mg,
47% from 8) as a white powder. X-ray crystal structure
determination was allowed after recrystallization from Et2O/
pentane. Colorless crystals. Rf ) 0.25. mp 88-89 °C. 1H
NMR: 3.88 (d, J ) 11.7 Hz, 1H), 3.75 (d, J ) 11.7 Hz, 1H),
2.67-2.65 (m, 1H), 2.55 (br, 1H), 2.35 (br, 1H), 2.26-2.25 (m,
1H), 1.64-1.60 (m, 2H), 1.45-1.52 (m, 2H), 1.15 (s, 3H), 1.04
(d, J ) 6.8 Hz, 1H).
Cycloa d d u ct 24. Irradiation of a solution of acetal 20b (64
mg, 0.22 mmol) in acetonitrile/acetone (15 mL, 9:1 v/v) for 75
min afforded 24 (64 mg, 100% crude yield) as a white powder.
The crude product was used immediately in the next reaction
without further purification. An analytically pure sample was
obtained after chromatography (EtOAc:PE ) 1:3) to afford 24
as a white powder. Rf ) 0.3. mp 126-127 °C. 1H NMR: 4.03-
3.82 (m, 4H), 3.13 (d, J ) 14.0 Hz, 1H), 2.76 (br d, J ) 9.0 Hz,
1H), 2.62 (d, J ) 14.0 Hz, 1H), 2.13 (dd, J ) 13.4, 6.6 Hz, 1H),
1.92 (dd, J ) 14.2, 5.8 Hz, 1H), 1.73-1.64 (m, 3H), 1.60 (s,
3H), 1.53 (s, 3H), 1.48 (s, 3H), 1.42-1.36 (m, 1H). 13C NMR:
169.9, 106.8, 104.0, 74.8, 67.4, 65.0, 64.6, 49.0, 39.0, 37.6, 29.2,
28.6, 27.7, 25.9, 25.6, 25.3. IR: 1729. HRMS (FAB) calculated
for C16H23O5 (MH+) 295.1545, found 295.1555.
3-Met h oxym et h oxy-4,6,8,8-t et r a m et h yl-7,9-d ioxa t r i-
cyclo[4.4.0.01,4]d eca n -10-on e (25). Irradiation of a solution
of alkene 18c (277 mg, 1.03 mmol) in acetonitrile/acetone (50
mL, 9:1 v/v) for 2-3 h afforded 25 (130 mg, 47%) as a colorless
oil after purification (EtOAc:PE ) 1:3). Rf ) 0.24. 1H NMR:
4.58 (d, J ) 6.6 Hz, 1H), 4.53 (d, J ) 6.6 Hz, 1H), 4.06 (dd, J
) 9.8, 6.7 Hz, 1H), 3.32 (s, 3H), 3.07 (dd, J ) 13.5, 9.8 Hz,
1H), 2.65 (d, J ) 13.2 Hz, 1H), 2.11 (dd, J ) 13.6, 6.8 Hz, 1H),
1-Hydr oxym eth yl-3-m eth oxym eth oxy-5-m eth ylbicyclo-
[2.1.1]h exa n -5-ol (16). The crude cycloadduct 15 (159 mg)
afforded a 50:50 mixture of diastereomers 16a and 16b (64
mg, 52% from 14) as a colorless oil after purification (EtOAc).
Rf ) 0.33. 16a : 1H NMR (C6C6): 4.52 (s, 2H), 4.05 (dd, J )
6.9, 1.6 Hz, 1H), 3.60 (s, 2H), 3.17 (s, 3H), 2.81-2.75 (m, 1H),
2.49-2.48 (m, 1H), 1.73 (ddd, J ) 11.8, 6.9, 3.0 Hz, 1H), 1.70
(d, J ) 6.6 Hz, 1H), 1.32 (dd, J ) 11.8, 2.0 Hz, 1H), 0.92 (s,

242 J . Org. Chem., Vol. 66, No. 1, 2001
Blaauw et al.
3H). 13C NMR (C6D6): 96.2, 84.8, 76.0, 63.1, 55.7, 55.3, 51.9,
37.3, 32.6, 18.8. 16b: 1H NMR (C6D6): 4.46 (s, 2H), 3.95 (ddd,
J ) 8.6, 2.9, 1.7 Hz, 1H), 3.67 (d, J ) 11.6 Hz, 1H), 3.53 (d, J
) 11.6 Hz, 1H), 3.15 (s, 3H), 2.81-2.75 (m, 1H), 2.45 (dd, J )
3.1, 1.6 Hz, 1H), 1.63 (dd, J ) 11.8, 8.6 Hz, 1H), 1.46 (ddd, J
) 11.8, 3.9, 3.1 Hz, 1H), 1.46 (s, 3H), 0.77 (d, J ) 7.0 Hz, 1H).
13C NMR (C6D6): 97.0, 85.2, 78.1, 63.1, 56.2, 55.8, 52.2, 36.6,
35.6, 34.4, 20.2. HRMS (FAB) calculated for C10H19O4 (MH+)
203.1283, found 203.1284.
ylic Acid Meth yl Ester (36). The crude cycloadduct 24 (56
mg, 0.19 mmol) afforded (105 min) a 50:50 mixture of two
diastereomers 36a and 36b (40 mg, 78% from 20b) as a
colorless oil after purification (Et2O:PE ) 1:3). Both isomers
were obtained pure after repeated chromatography. 36a : white
powder. Rf ) 0.21. mp 68-71 °C. 1H NMR: 3.94-3.70 (m, 4H),
3.58 (s, 3H), 2.89 (dd, J ) 9.3, 7.6 Hz, 1H), 2.45 (dd, J ) 12.6,
7.6 Hz, 1H), 2.40 (dd, J ) 12.6, 9.3 Hz, 1H), 2.29-2.23 (m,
1H), 2.12 (s, 3H), 2.01 (ddd, J ) 13.0, 10.2, 7.9 Hz, 1H), 1.83-
1.51 (m, 5H), 1.60 (s, 3H). 13C NMR: 221.1, 175.3, 109.0, 64.8,
64.4, 62.4, 51.6, 51.4, 37.5, 37.3, 32.2, 29.6, 28.6, 21.7. IR: 1728,
1708. HRMS (FAB) calculated for C14H21O5 (MH+) 269.1389,
found 269.1401. 36b: Colorless oil. Rf ) 0.13. 1H NMR: 3.96-
3.91 (m, 3H), 3.81-3.76 (m, 1H), 3.66 (s, 3H), 3.27 (dd, J )
7.8, 6.1 Hz, 1H), 3.09 (dd, J ) 9.7, 8.8 Hz, 1H), 2.60 (dd, J )
12.3, 9.7 Hz, 1H), 2.24 (s, 3H), 2.21 (dd, J ) 12.3, 8.7 Hz, 1H),
1,7a-Bis-h ydr oxym eth yl-8-m eth yloctah ydr o-1,3a-m eth -
a n oin d en e-3,8-d iol (32). The crude cycloadduct 3 (95 mg)
afforded the tetraol 32 (43 mg, 52% from 28) as a white powder
1
after purification (EtOAc:acetone ) 1:1). Rf ) 0.31. H NMR
(CD3OD): 4.38 (dd, J ) 11.4, 2.5 Hz, 1H), 3.94 (dd, J ) 7.4,
3.1 Hz, 1H), 3.77 (d, J ) 11.1 Hz, 1H), 3.38 (d, J ) 11.1 Hz,
1H), 3.34 (d, J ) 11.4 Hz, 1H), 3.26 (d, J ) 11.4 Hz, 1H), 3.03-
2.95 (m, 1H), 2.03-1.87 (m, 4H), 1.65-1.61 (m, 1H), 1.55-
1.25 (m, 4H), 1.08 (s, 3H). 13C NMR (CD3OD): 84.5, 73.0, 62.4,
59.1, 58.6, 58.1, 51.9, 37.6, 27.0, 23.0, 22.5, 21.9, 19.3. HRMS
calculated for C13H22O4Na (MNa+) 265.1416, found 265.1425.
Diol 33. Cycloadduct 23 (96 mg, 0.31 mmol) afforded diol
33 (78 mg, 99%) as a colorless oil without further purification.
1H NMR: 4.01-3.85 (m, 4H), 3.81-3.75 (m, 2H), 2.62 (dd, J
) 8.8, 6.4 Hz, 1H), 2.55 (d, J ) 13.9 Hz, 1H), 2.40-2.20 (br,
2H), 2.20 (d, J ) 13.9 Hz, 1H), 1.81-1.73 (m, 2H), 1.70-1.43
(m, 3H), 1.37-1.26 (m, 1H), 1.27 (s, 3H), 1.14-1.06 (m, 1H).
13C NMR: 109.1, 79.4, 64.5, 64.3, 62.7, 51.6, 45.1, 40.7, 40.5,
24.0, 21.5, 20.8, 19.5, 18.3. HRMS (FAB) calculated for
2.14-2.08 (m, 1H), 1.86-1.81 (m, 1H), 1.75-1.50 (m, 4H). 13
C
NMR: 210.6, 172.8, 108.6, 64.9, 64.5, 63.1, 53.4, 51.4, 36.3,
36.2, 31.3, 29.7, 28.2, 23.0. IR: 1733, 1702.
3-Meth oxym eth oxy-2-m eth yl-2-(2-oxop r op yl)cyclobu -
ta n eca r boxylic Acid Meth yl Ester (37). The product from
the basic treatment required heating in refluxing THF to
undergo the retro-aldol reaction. The cycloadduct 25 (81 mg,
0.3 mmol) afforded (30 min) a 30:70 mixture of diastereomers
37a and 37b (56 mg, 77%) as a colorless oil after purification
(Et2O:PE ) 1:4). Both isomers were obtained pure after
repeated chromatography. 37a : Colorless oil. Rf ) 0.15. 1H
NMR: 4.55 (d, J ) 6.6 Hz, 1H), 4.50 (d, J ) 6.6 Hz, 1H), 3.74
(dd, J ) 8.7, 7.4 Hz, 1H), 3.63 (s, 3H), 3.34 (s, 3H), 2.80 (d, J
) 18 Hz, 1H), 2.64 (d, J ) 18 Hz, 1H), 2.44 (dd, J ) 10.8, 7.5
Hz, 1H), 2.34-2.24 (m, 2H), 2.11 (s, 3H), 1.44 (s, 3H). 13C
NMR: 207.2, 173.3, 96.7, 76.3, 55.3, 51.5, 48.8, 42.5, 40.6, 28.4,
26.1. IR: 1731. HRMS (FAB) calculated for C12H21O5 (MH+)
245.1389, found 245.1382. 37b : Colorless oil. Rf ) 0.10. 1H
NMR: 4.56 (d, J ) 6.5 Hz, 1H), 4.53 (d, J ) 6.5 Hz, 1H), 3.98
(ddd, J ) 7.0, 5.2, 1.0 Hz, 1H), 3.68 (s, 3H), 3.32 (s, 3H), 3.01
(ddd, J ) 9.3, 5.9, 1.0 Hz, 1H), 2.80 (d, J ) 16.8 Hz, 1H), 2.68
(d, J ) 16.8 Hz, 1H), 2.54 (ddd, J ) 12.8, 7.1, 5.9 Hz, 1H),
C
14H23O4 (MH+) 255.1596, found 255.1591.
Rep r esen ta tive P r oced u r e for th e Retr o-Ald ol Rea c-
tion . To a solution of cycloadduct 3 (100 mg, 0.34 mmol) in
dioxane (10 mL) at room temperature was added dropwise an
aqueous solution of KOH (1.8 mL, 10% w/w). The mixture was
stirred for 150 min. The reaction mixture was cooled to 0 °C,
acidified carefully with 2 N HCl to pH 2-3, and extracted with
CH2Cl2. The combined organic layers were washed brine, dried
over MgSO4, and concentrated in vacuo. The remaining
mixture was dissolved in methanol (5 mL), cooled to 0 °C, and
treated with an excess of diazomethane. After concentration
in vacuo, the crude oil was purified by chromatography
(EtOAc:PE ) 1:1) to afford 6-a cetyl-9-oxo-8-oxa tr icyclo-
[5.2.2.01,6]u n d eca n e-10-ca r boxylic a cid m eth yl ester 34
(71 mg, 78%) as a white powder. Rf ) 0.22. mp 144-146 °C
(EtOAc/pentane). 1H NMR: 4.75 (br, 1H), 3.69 (s, 3H), 3.29
(dd, J ) 10.3, 4.5 Hz, 1H), 2.48 (ddd, J ) 14.4, 4.5, 1.0 Hz,
1H), 2.19-2.15 (m, 2H), 2.15 (s, 3H), 1.96 (ddd, J ) 6.6, 3.3,
1.3 Hz, 1H), 1.89 (ddd, J ) 14.4, 10.3, 2.0 Hz, 1H), 1.74-1.57
(m, 3H), 1.45-1.33 (m, 1H), 1.05 (dq, J ) 13.7, 3.6 Hz, 1H).
13C NMR: 205.2, 175.1, 171.8, 78.7, 67.4, 56.8, 52.3, 42.7, 31.6,
25.6, 25.6, 22.3, 21.8, 20.1. IR: 1775, 1732, 1705. Anal. Calcd
for C14H18O5: C, 63.15; H, 6.81. Found: C, 62.98; H, 6.93.
7-Acetyl-1,4-d ioxa d isp ir o[4.0.5.2]tr id eca n e-12-ca r box-
ylic Acid Meth yl Ester (35). The crude cycloadduct 23 (43
mg, 0.14 mmol) afforded (105 min) a 30:70 mixture of two
diastereomers 35a and 35b (30 mg, 75%) as a colorless oil after
purification (EtOAc:PE ) 1:5). Both isomers were obtained
pure after repeated chromatography. 35a : colorless oil. Rf )
2.15 (s, 3H), 2.01 (ddd, J ) 12.7, 9.3, 5.2, 1H), 1.16 (s, 3H). 13
C
NMR: 207.2, 173.9, 95.6, 77.3, 55.4, 51.4, 48.0, 46.0, 42.7, 31.4
27.3, 20.6. IR: 1733 (br).
3-Meth oxym eth oxy-2-(1-m eth yl-2-oxop r op yl)cyclobu -
ta n eca r boxylic Acid Meth yl Ester (38). The cycloadduct
mixture (70:20:10) 26 (22 mg, 0.08 mmol) afforded (45 min) a
70:30 mixture of two main diastereomers 38a and 38b (15 mg,
75%) as a colorless oil after purification (Et2O:PE ) 1:3). Both
isomers were obtained pure after repeated chromatography.
1
Ma in isom er 38a : Colorless oil. Rf ) 0.12. H NMR: 4.64 (d,
J ) 6.7 Hz, 1H), 4.56 (d, J ) 6.7 Hz, 1H), 4.32-4.26 (m, 1H),
3.59 (s, 3H), 3.57 (s, 3H), 3.13-3.06 (m, 1H), 2.99 (ddd, J )
8.8, 7.9, 0.9 Hz, 1H), 2.38-2.34 (m, 2H), 2.17-2.14 (m, 1H),
2.15 (s, 3H), 1.13 (d, J ) 7.0 Hz, 3H). 13C NMR: 211.5, 174.3,
94.6, 70.5, 55.5, 51.4, 45.2, 42.9, 35.5, 30.7, 28.3, 16.3. IR: 1714,
1712. HRMS (FAB) calculated for C12H21O5 (MH+) 245.1389,
1
found 245.1383. 38b: Colorless oil. Rf ) 0.08. H NMR: 4.66
(d, J ) 6.7 Hz, 1H), 4.53 (d, J ) 6.7 Hz, 1H), 4.34 (ddt, J )
6.6, 2.3, 0.9 Hz, 1H), 3.67 (s, 3H), 3.37 (s, 1H), 3.03 (ddt, J )
9.1, 8.2, 0.9 Hz, 1H), 2.95 (dq, J ) 10.6, 6.8 Hz, 1H), 2.88-
2.82 (m, 1H), 2.35 (ddd, J ) 12.5, 8.2, 1.0 Hz, 1H), 2.17-2.11
(m, 1H), 2.14 (s, 3H), 1.57 (s, 3H), 1.12 (d, J ) 6.8, 3H). 13C
NMR: 211.2, 174.9, 94.5, 71.2, 55.6, 51.6, 46.0, 45.5, 40.0, 30.1,
28.3, 15.1. IR: 1734, 1711.
1
0.17. H NMR: 3.96-3.75 (m, 4H), 3.56 (s, 3H), 2.60 (dd, J )
9.6, 8.0 Hz, 1H), 2.42 (dd, J ) 7.9, 12.6 Hz, 1H), 2.33 (dd, J )
9.6, 12.6 Hz, 1H), 2.21-2.12 (m, 1H), 2.10 (s, 3H), 1.94-1.90
(m, 2H), 1.72 (ddt, J ) 13.9, 5.8, 3.5 Hz, 1H), 1.60-1.56 (m,
2H), 1.45-1.38 (m, 1H), 1.32 (qt, J 13.0, 4.0 Hz, 1H), 1.06 (qt,
J ) 13.2, 3.6 Hz, 1H). 13C NMR: 210.5, 174.8, 108.3, 64.6, 64.3,
55.9, 51.3, 47.3, 40.6, 36.7, 29.9, 29.0, 26.1, 23.9, 21.1. IR: 1723
(br). HRMS (FAB) calculated for C15H23O5 (MH+) 283.1545,
found 283.1540. 35b: X-ray crystal structure determination
was allowed after recrystallization from EtOAc/PE. Colorless
crystals. Rf ) 0.08. mp 85-87 °C. 1H NMR: 3.94-3.68 (m,
4H), 3.67 (s, 3H), 3.53 (semit, 1H), 2.70 (dd, J ) 7.2, 4.1 Hz,
1H), 2.58 (dd, J ) 12.6, 9.2 Hz, 1H), 2.19 (s, 3H), 2.14 (dd, J
) 12.6, 9.0 Hz, 1H), 2.07-2.02 (m, 1H), 1.64-1.50 (m, 5H),
1.27-1.24 (m, 2H). 13C NMR: 211.1, 174.0, 109.1, 64.7, 64.3,
56.9, 51.6, 51.4, 36.2, 35.2, 30.4, 27.1, 26.4, 23.9, 21.9. IR: 1731,
1711.
Ack n ow led gm en t. These investigations are sup-
ported (in part) by The Netherlands Research Council
for Chemical Sciences (CW) with financial aid from The
Netherlands Technology Foundation (STW).
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of diols 10 and 16, cycloadducts 21-26, 3, and 4, and
tetraol 32. Tables of X-ray crystallographic data of compounds
10, 3, 4, and 35. This material is available free of charge via
the Internet at http://pubs.acs.org.
7-Acetyl-1,4-d ioxa -d isp ir o[4.0.4.2]d od eca n e-11-ca r box-
J O0056500