Synthesis and biological studies of flexible brevetoxin/ciguatoxin models with marked conformational preference

Article abstract of DOI:10.1016/S0040-4020(02)00047-9

A comparison of the more active polyether toxins which are selective activators of voltage-sensitive sodium channels (VSSC), indicate that these molecules are mostly flat, with a hinge part around the middle of the molecules and a large curvature at one of the ends. Assuming that the receptor is topographically complementary to the active molecules, from the result reported here we could conclude, that the specific requirements of the receptor region can be achieved by synthetic polyether models based on exclusive participation of oxane/oxepane moieties. A new convergent approach to give oxepene rings via double reduction of methyl diacetals is explored. In searching for biological models to further characterize Na⁺ channels, our studies show that different voltage-dependent Na⁺ channels are expressed in the rat uterus and activated by brevetoxin-B. However, selected compound models synthesized in this work, failed to inhibit or activate Na⁺ channel function.

Full text of DOI:10.1016/S0040-4020(02)00047-9

TETRAHEDRON
Pergamon
Tetrahedron 58 52002) 1921±1942
Synthesis and biological studies of ¯exible brevetoxin/ciguatoxin
models with marked conformational preference
M. L. Candenas,a,p Francisco M. Pinto,a Cristina G. Cintado,a Ezequiel Q. Morales,a,p
a
a
b
b
Ignacio Brouard, M. Teresa Dõaz, Milagros Rico, Elsa Rodrõguez, Rosa M. Rodrõguez,
a
Â
Ricardo Perez, Ruby L. Perez and Julio D. Martõn
Â
Â
a
a
a,p
Â
Â
Â
a
 Â
Instituto de Investigaciones Quõmicas, CSIC, Avda. Americo Vespucio, s/n, Isla de la Cartuja, 41092 Seville, Spain
Â
Departamento de Quõmica, Universidad de Las Palmas, Campus de Ta®ra, 35107 Las Palmas de Gran Canaria, Spain
b
Received 8 October 2001; accepted 20 November 2001
AbstractÐA comparison of the more active polyether toxins which are selective activators of voltage-sensitive sodium channels 5VSSC),
indicate that these molecules are mostly ¯at, with a hinge part around the middle of the molecules and a large curvature at one of the ends.
Assuming that the receptor is topographically complementary to the active molecules, from the result reported here we could conclude, that
the speci®c requirements of the receptor region can be achieved by synthetic polyether models based on exclusive participation of oxane/
oxepane moieties. A new convergent approach to give oxepene rings via double reduction of methyl diacetals is explored. In searching for
biological models to further characterize Na1 channels, our studies show that different voltage-dependent Na1 channels are expressed in the
rat uterus and activated by brevetoxin-B. However, selected compound models synthesized in this work, failed to inhibit or activate Na1
channel function. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
other presently known compounds are not able to discrimi-
nate between different Na1 channel subtypes.6 This is one of
the reasons justifying our presently poor knowledge of Na1
channel characterization and classi®cation. In searching for
selective compounds for a certain Na1 channel, a main
objective would be the chemical modi®cation of these
known compounds, in order to establish structure±activity
relationships and look for analogues with increasing selec-
tivity, able to discriminate between different Na1 channel
isoforms. A second objective would be to ®nd simple bio-
logical models that would permit us to study the activity of
different compounds on a particular channel subtype. As an
example to illustrate the complexity of the subject, Fig. 1
shows Na1 channel messenger RNA 5mRNA) expression in
the non-pregnant rat uterus. The myometrium is unique
among most mammalian visceral smooth muscles in that
it contains voltage-gated Na1 channels.7 Fig. 1 shows that
many Na1 channels are expressed in the uterus, giving an
idea of the dif®culty of establishing a precise correlation
between a functional response and the speci®c Na1
channel5s) subtype5s) involved in this response.
The propagation of electrical signals in excitable cells is
mediated through the gating of membrane-associated ion
channels. These proteins, that show ion selectivity for K1,
Na1 or Ca21, are all composed of four identical or similar
subunits, each containing six transmembrane segments in a
roughly four-fold symmetric structure.1 Among them,
voltage-dependent Na1 channels are a main component
for the generation of the rapid depolarization during the
initial phase of the action potential.2 At least 10 different
voltage-operated Na1 channel subtypes have been cloned in
mammals and the number will probably increase.3 Changes
in the expression and/or function of these proteins represent
an important step in the development of different patholo-
gies and, consequently, it is essential to ®nd compounds
able to act selectively as openers or inhibitors of a certain
Na1 channel subtype.4
Probably due to their central role in neurotransmission,
voltage-gated Na1 channels are the target of many natural
toxins, that are able to interact with the protein or even to
mimic its membrane disposition, forming arti®cial ion
channels.5 These Na1 channel-speci®c natural toxins have
been very useful tools for understanding the structure and
function of the channel. However, most of these toxins and
Examples of molecules of interest to us include the confor-
mationally constrained polyethers: brevetoxins 5BTXs) and
ciguatoxins 5CTXs),8,9 which are selective activators of
voltage-sensitive sodium channels 5VSSC) in nerves, heart
and muscle.10 The binding of both groups of polyethers
induces a conformational change in the organization of
the protein which tends to stabilize a multiplicity of
different open and/or preopen states of the channel. In
Keywords: sodium channels; uterus; toxins; conformation; polyethers.
Corresponding authors. Tel.: 134-95-4489565; fax: 134-95-4460565;
e-mail: mluz@cica.es; ezequiel@iiq.cartuja.csic.es; jdelgado@cica.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020502)00047-9

1922
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
Figure 1. Agarose gel showing products of reverse-transcriptase-polymerase chain reaction 5RT-PCR) assay for cDNA from non-pregnant rat uterus in the
estrous stage of the ovarian cycle. Equal amounts of uterine cDNA, as determined from the previous ampli®cation of the housekeeping genes glyceraldehyde
3-phosphate dehydrogenase 5GAPDH) and b-actin, were ampli®ed with primers speci®c for each of the rat voltage-dependent Na1 channel a subunits. Single
transcripts corresponding to the sizes predicted for the tetrodotoxin 5TTX)-sensitive Na1 channels from skeletal muscle SKM1m1 5lane 2), PN4a 5lane 3), and
brain type II 5lane 6) and III 5lane 5) were expressed in the uterus. The TTX-insensitive SNS2 5lane 9) and the atypical SCL11 5lane 1) were also detected. The
speci®c bands corresponding to the TTX-sensitive channels SCN9A 5lane 4) and brain type I 5lane 7) and the TTX-insensitive SKM2 5lane 8) and SNS 5lane 10)
channels were undetected. M represents molecular size standards.
consequence, BTXs and CTXs shift the voltage dependence
of the activation kinetics and eliminate the inactivation of
the Na1 current inducing a persistent activation of the
channel. Both groups of lipid-soluble toxins are trans-
fused polycyclic systems composed of a single carbon
chain that winds the length of the molecule. In each toxin
structure, the chain is linked by ether oxygens into a series
of trans/syn-fused cyclic arrays, with ring sizes ranging
from ®ve- to nine-membered oxacycles. The structural
requirements for the toxicity are complex, involving stereo-
chemistry, length and conformational ¯exibility of the
BTXs and CTXs are thus examples of ¯exible molecules
with a de®ned shape; that is, compounds that essentially
populate a single conformation, whilst maintaining full
conformational ¯exibility. Because ligand ¯exibility
strongly in¯uences receptor binding, an important question
concerns the biological relevance of the compact folded
region in the more active polyethers; i.e. H/N-rings segment
of the C-CTX-19k 5Fig. 2). The results reported later repre-
sent an attempt to discover easily accessible structural
oxane/oxepane segments that, in the context of trans-
fused polyethers, form the basis for the design of BTX/
CTX mimetics.
Ê
whole molecule. Because polyether size 5,30 A long) and
¯exibility 5seven- to nine-membered oxacycles) strongly
in¯uences receptor binding, internal motions of natural
toxins have been thoroughly investigated by experimental
and computational methods.6,11 It has been proposed that the
`ideal' pharmacophore is a roughly `hair-pin' shaped lipid
2. Results and discussion
2.1. Conformational background
Ê
soluble molecule, .30 A long, bound to its receptor pri-
marily with hydrophobic and non-polar solvation forces,
possible aided by strategically placed ether oxygens acting
as hydrogen bond acceptors being their effectiveness
5CTXs@BTXs) depending on their selectivity for the active
conformation of the receptor.
In general, modeling structurally complex compounds for a
biological study requires parallel consideration of confor-
mation and synthetic principle, to ensure a successful
outcome. Because of the extra ring bond, oxepane has one
more degree of torsional freedom as compared with its
lower oxane homologue and, therefore, no rigid confor-
mation of oxepane exists.12 There are, however, two confor-
mational families that cannot be interconverted without
increasing bond angles, just as in an oxane. One family
consist of the chair, the twist-chair and all the intermediate
forms between these; the other family may be similarly
described in terms of a boat and twist-boat. According to
molecular mechanics calculations, there is a substantial
barrier, about 9.0 kcal/mol, preventing the interconversions
belonging to the two families, but very low barriers to
pseudorotation 52±3 kcal/mol) within either family.
However, all the evidence is consistent with the oxepane
existing largely in the twist-chair conformations.13
When torsional constrains are introduced in a seven-
membered ring, the conformational picture becomes
analogous to that of cyclohexane, and both geometrically
rigid and ¯exible forms occur. Dreiding molecular models
show that in tricyclic trans, syn, trans-fused oxane/oxepane/
oxane systems, only chair and twist-chairs are possible for
the internal oxepane ring.14 Non-eclipsed twist-chair forms
of oxepane are in fact the minimum-energy conformations,
Figure 2. 5A) Caribbean ciguatoxin-1 5C-CTX-1). 5B) Conformational
behavior of the lower energy conformer.9k Copyright 51998) American
Chemical Society. Reprinted with permission.

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1923
Figure 3. Possible conformers for an oxatricyclic trans,syn,trans-fused polyether possessing an internal oxepane ring.
whereas the chairs are transition states for the slightly
hindered pseudorotations that occur to relieve the eclipsing
strains. Fig. 3 illustrates the three possible chair conformers
for the internal oxepane in a trans, syn, trans-fused oxa-
Fused oxepane rings present an interesting conformational
problem. Although each ring might be expected to have a
number of accessible chair and twist-chair conformation,
we are unsure what effect their fusion might have on the
potential energies of various 5reasonable) conformations.
While fused oxane rings always gave rigid and extended
conformations, by virtue of their trans decalin-like geo-
metry, we were uncertain about fused oxepanes ¯anked by
¯exible 5oxepanes and higher size rings) or rigid 5oxanes)
moieties. We decided to ®rst address this question by syn-
thesis and conformational study of a wide range of model
compounds, a selection of which are included in Table 1.
tricyclic system.15 Each of these chairs 52,3C6, a2,3
±
ˆ
4,5
0
1858 and C3,4, a2,3
±
ˆ08; 4,5C1, a2,3
±
ˆ2858) and
4,5
4,5
their minimum energy twist-chair conformers 55,6TC0,1,
a2,3
±
ˆ1358 and 1,2TC6,0, a2,3
±
ˆ2358), may be inter-
4,5
4,5
converted by folding the oxatricyclic molecule in a direction
depending on the con®guration of the oxepanyl moiety.
Consequently, the introduction of seven-membered ring
oxacycles in the middle of rigid trans-fused polyethers
should be a way to create ¯exible polyethers with pre-
dictable conformational pro®les 5Fig. 4).
2.2. Synthesis and conformational pro®le of trans-fused
oxane/oxepane systems
Related ¯exible moieties in the middle of rigid backbones
are a common feature of brevetoxins and ciguatoxins and
are suspected to play a role in the bioactivity of these toxins.
However, no conformational studies in solution have
yet been performed, probably due to the scarcity of these
polyethers from natural sources.
The synthesis of ortho-condensed compounds containing
oxepane rings ¯anked by different sized oxacycles would
be useful for the thermodynamic analysis of their charac-
teristic conformational behavior described earlier. As a part
of our studies directed toward the synthesis of brevetoxin/
Figure 4. Conformational pro®le of trans,syn,trans-fused oxane/oxepane polyethers and their folded dependence with the con®guration of the oxepane rings.
Colors associated with twist-chairs in the direction in which molecules are folded 5X blue, up; X red, down).

1924
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
Table 1. Conditions: 0.2±0.5 mmol scale, 10±30 mol% of [5PCy3)2RuCHPh]Cl2, 6£1023 M 5CH2Cl2), 258C, 2±4 h
Entry
Substrate
Product
Yield 5%)
1
.95
2
3
4
5
6
7
.95
.95
.95
.95
.95
.95
ciguatoxin mimetics, we have developed a cyclization
methodology for assembling ether rings of various sizes
from simple cycloalkenes, in the trans-relationship that is
found in natural polyethers.16 Herein, we describe ®rst the
synthesis of selected tri- tetra- and penta-cyclic model
compounds 5Table 1), including studies related to their
conformational behavior at room temperature based on
NMRspectroscopy. As illustrated in Table 1, compounds
8±14 were achieved, in essentially quantitative yield, by
ring-closing metathesis 5RCM) from their respective alkyl-
idene precursors 1±7,17 using bis 5tricyclohexyl-phosphine)
benzylidene ruthenium dichloride as catalyst.18 The meso
Scheme 1. Reagents and conditions: 5a) 5i) 0.2 equiv. OsO4, 5.0 equiv. NMO, acetone/H2O 54:1); 5ii) 1.5 equiv. NaIO4, acetone/H2O 59:1), 88% 5two steps);
5b) 2.5 equiv. of PPh3CH3Br, 2.5 equiv. of n-BuLi, THF, 0±258C, 8 h, 84%; 5c) 2.5 equiv. of n-Bu4NF, THF, 258C, 2 h 519: 98%; 23: 98%; 28: 97%);
5d) 10.0 equiv. of allyl bromide, 2.5 equiv. of NaH, n-Bu4NI catalyst, THF, 0±258C, 8 h 53: 88%; 2: 92%; 1: 89%); 5e) 6.0 equiv. of NaBH4, MeOH, 08C, 1 h
520: 94%; 25: 96%); 5f) 4.0 equiv. of I2, 3.0 equiv. of imidazole, 5.0 equiv. of PPh3, C6H6, 48C, 1 h 521: 98%; 26: 96%); 5g) 2.5 equiv. of KO±t-Bu, THF, 258C,
30 min 522: 93%; 27: 89%); 5h) O3, CH2Cl2, 2788C, 20 min, then 3.0 equiv. of PPh3, 208C, 1 h, 87%.

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1925
5for compounds 5, 6) and 2-deoxy-d-ribose 5for com-
pound 7).
Analysis by NMRspectroscopy reveal that, with exception
of compounds 13 and 14, cyclization to give terminal oxane
1
rings occurs with concomitant sharpening of the H NMR
1
signals. As an example, Fig. 5 show the H NMRspectra
corresponding to the methylene protons of oxepane rings of
the pentacyclic compound 11 in comparison with its tri-
cyclic precursor 4. Since sharpened peaks are thought to
be derived from single conformers, oxepane rings in 11
are assumed to mostly exist in a dominant conformation at
room temperature.
Modeling of compound 11 reveals a marked conformational
preference for the whole molecule, which is due to an
ordered alternation of twist-chair/chair conformers for the
oxepane rings. Table 2 includes calculated lower-energy
conformers of 11 which show twist-chair conformations
for both oxepanes adjacent to oxene rings 5ring 1, 3 in
11), whereas the middle oxepane 5ring 2 in 11) appears
to be ®xed in chair conformations. Since change among
twist-chair, 5,6TC0,1 and 1,2TC6,0 or extended chairs 2,3C6
and 4,5C1 does not alter the overall pro®le of the molecule
5Fig. 3), the minimum-energy conformers should be
virtually superimposable, which results in a semirigid
C-shaped pro®le for the whole structure.
Furthermore, NOE and coupling-constant data were used
together with molecular modeling to establish the average
conformation in solution for the pentacyclic compound 11
5Fig. 6). Low-energy conformer were obtained in all cases
from a Monte Carlo search as it is implemented in Macro-
model.21 Examination of the low-energy population
revealed that 97.9% is occupied by two essentially iso-
energetic 5DEˆ0.03 kcal/mol) and almost superimposable
conformers, which correspond to the C-shaped structure
depicted in Fig. 6a. A comparison of 11 with its tricyclic
precursor 4 5diacetate), Fig. 6b, shows that the absence of
the strain imposed by fusion with external oxane rings,
allows a mostly ¯at and ¯exible oxepanyl segment due to
1
Figure 5. H NMR5CDCl ) corresponding to methylene oxepane protons
of compounds 4 5A) and 11 5B).
3
compounds 1±4 5entries 1±4) were prepared from 5E, E, Z)
cyclododecatriene 515)19 following the synthetic sequence
outlined in the Scheme 1. Compounds 5±7 5entries 5 and
6) were synthesized20 starting from tri-O-acetyl-d-glucal
Table 2. Low-energy conformers for compound 11 5Cˆchair; TCˆtwist-chair), T1, T2, T3 are torsion angle a2,3
5blue) associated with twist-chairs in the direction in which the molecule is folded
±4,5 for oxepane rings 1, 2, 3, respectively; color
Conf.
1
DE 5kJ/mol)
T1
T2
T3
Conformational pro®le
0
236.7
88.0
229.7
2
3
4
0.03
2.64
2.65
29.7
32.9
29.9
288.3
290.0
290.0
37.3
229.9
32.9
C-shaped structure 5semi-rigid)

1926
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
Figure 6. 5A) Low-energy conformation of compound 11. 5B) Low-energy conformation of compound 4 5diacetate).
preferentially extended chair conformations 2,3C6 and 4,5C1
of the seven-membered oxacycles 5conformer population
82.2%).
distinguishable six-membered 5oxene and 1,3-dioxane)
rings. For compound 14, as occurs with its related 13,
although the average structure can be determined with
®delity, detailed proton signals of each oxepane cannot be
quanti®ed by 1H NMRspectra. The broadened proton
resonance of the methylene hydrogens in compound 14 indi-
cated the conformational change of the oxepane rings on a
millisecond time scale. Table 3 shows the lower-energy
conformers calculated for compound 14. As expected several
chairs and twist-chair conformations for each oxepane were
indiscriminately found forming a highly ¯exible S-shaped
structure. Indeed, this result is in agreement with the reported
modeling of brevetoxin-B,22 which shows a ¯exible back-
bone around the two seven-membered moieties.
Compound 14 possesses two fused oxepanes ¯anked by two
Table 3. Low-energy conformers for compound 14 5Cˆchair; TCˆtwist-
chair), T1,T2 are torsion angle a2,3±4,5 for oxepane rings 1, 2, respectively;
color associated with twist-chairs and the direction in which molecule is
folded 5 blue, up;
red, down)
In consonance with the earlier results, a semirigid C-shaped
structure should be expected for the heptacyclic derivative
29, where ®ve oxepanes are ¯anked by two terminal oxenes.
Conf. DE 5kJ/mol)
T1
T2
Conformational pro®le
1
2
3
4
5
0
283.3
29.3
1
Indeed, both H and 13C NMRsignals arising from the
oxepanyl moiety in 29,23 were observed without signi®cant
peak broadening. As the individual conformation of these
oxepanes is important in order to stabilize the overall shape
of the molecule, molecular mechanics studies were carried
out. Table 4 shows the calculated lower energy conformers
for compound 29, which reveal twist-chairs conformers for
the middle oxepane and the two oxepanes adjacent to
oxenes 5rings, 1, 3, 5 in 29), and extended chair confor-
mations for the two others seven-membered rings 5rings 2,
4 in 29). These results reveal a monoconformational and
semirigid C-shaped structure for compound 29.
2.73
4.54
5.45
9.33
28.7
81.7
283.1
45.9
211.2
246.0
34.8
79.2
S-shaped structure 5¯exible)

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1927
Table 4. Low-energy conformers for compound 29 5Cˆchair, TCˆtwist-chair), T1, T2, T3, T4, T5 torsion angle a2,3
respectively. Color, 5blue) associated with twist-chairs show the direction in which the molecule is folded
±
for oxepane rings 1, 2, 3, 4, 5,
4,5
a
Ê
Length 5A)
Conf.
DE 5kJ/mol)
T1
T2
T3
T4
T5
1
2
3
4
5
6
7
8
0
236.8
236.6
236.8
29.7
236.6
32.9
229.5
235.7
32.8
228.9
235.6
228.9
228.9
88.0
88.2
88.0
288.0
88.2
89.7
288.1
86.7
89.8
286.4
86.6
286.5
286.4
33.0
225.1
231.9
37.2
225.7
233.6
236.4
24.3
223.8
35.7
25.7
32.4
35.0
88.1
286.6
86.4
229.7
35.5
28.8
229.9
232.3
229.7
229.7
229.9
38.5
229.9
29.3
233.0
29.4
15.92
15.65
15.86
16.60
15.77
16.18
16.47
16.28
25.80
16.45
16.28
16.11
16.31
1.6
1.6
4.0
4.3
4.3
4.5
5.4
5.5
5.9
5.9
6.1
6.2
89.7
288.3
88.2
88.1
89.7
9
286.8
89.7
88.1
289.7
88.1
10
11
12
13
Conformational pro®le
C-shaped structure 5semi-rigid)
a
Length refers to distance among oxene oxygens and was calculated by molecular mechanics routine.
In conclusion, the study reported here provides logical
starting points for the development of ¯exible 5S-shaped)
or semirigid 5C-shaped) polycycles. From these results we
can expect that the speci®c topographical requirements
present in natural polyethers may be achieved in synthetic
models based on oxane/oxepane segments.
ethers via reductive etheri®cation to oxane26 and oxocene25
ring systems, cyclization to oxepanes is a limitation of the
method due to the dif®culty in directing the stereoselectivity
toward the required trans±syn±trans-epimer.28 We report
below studies related to the steroselective construction of
the trans-fused mixed diacetal 30 and double reductive
etheri®cation to the trans-fused oxepanyl system 31
5Scheme 2).
Ê
In order to reach the required polyether size 5,30 A long),
pairs of the above fragments can be coupled with version of
convergent approaches24 to give series of polycyclic models
with different lengths and conformational mobility. This
knowledge could, in principle, be used to limit the structures
of synthetic molecules to those optimally ®t for binding. We
next report on the synthesis of oxepane rings following a
convergent methodology.25±27
The coupling of intermediates 3229 and 3330 and elaboration
of the resulting product to compound 47 is summarized in
Scheme 3. The lithium acetylide obtained from n-butyl-
lithium addition to 32 5n-BuLi, THF, 278 to 408C) was
quenched with lactone 33 to afford 34 as an inseparable
mixture of diastereomers at C-1 in 90% yield.28b Treatment
of the 1:1 mixture of hemiacetals 34 with CSA in methanol
at 08C gave a 1:1 mixture of mixed acetals 35 and 36 which
were separated by ¯ash column chromatography. The acid
catalyzed reaction occurs with concomitant loss of TBS
group in 98% yield. Acetylation of 35 5or 36) afforded
37 5or 38), which were then further treated with 10%
Pd±BaSO4 under hydrogen atmosphere to give 39 5or 40)
in 64% yield. Compounds 39 and 40 were oxidized to
ketones 41 and 42 which were, respectively, hydrolyzed
by base treatment to the hydroxy-ketone 43 574% yield,
two steps) and hemiacetal 44 568% yield, two steps).
When compounds 43 and 44 were independently subjected
to reductive 5SI-LA) conditions using Et3SiH/BF3´OEt2, an
identical mixture of oxatricycles 46 and 47 582% yield; ca
9:1) was obtained. The stereochemistry of compounds 46
and 47 was easily determined by 2D COSY and NOESY
NMRexperiments. The manner of fusion and stereo-
2.3. Synthesis of oxane/oxepane models via a convergent
approach
The reductive intramolecular coupling of hydroxy-ketones
in reactions with silane-Lewis acids 5SI-LA) to generate
cyclic ethers is affected by the conformational preference
of the hemiacetal 5or mixed acetal or thioacetal) inter-
mediates.24 Although this method has presented a powerful
tool for ef®cient convergent synthesis of trans-fused poly-
1
chemistry in 46 were clari®ed by 1D HNOE difference
measurements and JH,H data. Prominent enhancements in
Scheme 2.

1928
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
Scheme 4. Reagents and conditions: 5a) 2.0 equiv. of n-BuLi, THF, 278 to
2358C, 1 h, then 0.96 equiv. of 51, 258C, 1.5 h, 93%; 5b) 0.3 equiv. of CSA,
MeOH, 258C, 12 h, 96%; 5c) 3.0 equiv. of Ac2O, 3.0 equiv. of Et3N, DMAP
catalyst, CH2Cl2, 258C, 6 h, 98%; 5d) 10% Pd±BaSO4 catalyst, 0.1 equiv. of
quinoline, H2, EtOAc, 258C, 5 h, 59%; 5e) 3.4 equiv. of oxalyl chloride,
5.8 equiv. of DMSO, 11.0 equiv. of Et3N, CH2Cl2, 2788C, 1.5 h, 82%; 5f)
0.5 equiv. of MeONa, MeOH, 258C, 30 min, 57 and 58 51:1 ratio), 86%; 5g)
2.5 equiv. of NaH, 5.0 equiv. of MeI, DMF, 08C, 6 h; 53%; 5h) 14.5 equiv.
of Et3SiH, 15.0 equiv. of BF3´OEt2, MeCN, 278 to 2308C, 2 h, 57%; 5i)
from 57, 15.0 equiv. of Et3SiH, 15.0 equiv. of BF3´OEt2, MeCN, 08C, 12 h
563: 66%; 64: 11%); from 58 563: 75%; 64: 9%); 5j) from 57, 15.0 equiv. of
BF3´OEt2, MeCN, 2158C, 1 h, 61 and 62 51:1 ratio), 100%.
Scheme 3. Reagents and conditions: 5a) 0.3 equiv. of CSA, MeOH, 258C,
24 h, 98%, compounds 35 and 36 51:1 ratio); 5b) 3.0 equiv. of Ac2O,
4.0 equiv. of Et3N, DMAP catalyst, CH2Cl2, 258C, 6 h 537: 97%; 38:
94%); 5c) 10% Pd±BaSO4, catalyst, 0.1 equiv. of quinoline, H2, EtOAc,
258C, 6 h 539: 64%; 40: 59%); 5d) 3.4 equiv. of oxalyl chloride, 5.7 equiv.
of DMSO, 11.4 equiv. of Et3N, CH2Cl2, 2788C, 1 h 541: 76%; 42: 79%); 5e)
0.4 equiv. of MeONa, MeOH, 258C, 30 min 543: 80%; 44: 94%); 5f)
2.5 equiv. of NaH, 5.0 equiv. of MeI, DMF, 08C, 8 h, 61%; 5g) from 43,
15.0 equiv. of Et3SiH, 15.0 equiv. of BF3´Et2O, MeCN, 08C, 3 h 546: 73%;
47: 8%); from 44 546: 72%; 47: 8%); from 48 546: 74%; 47: 9%); from 49
546: 74%; 47: 9%); 5h) 15.0 equiv. of Et3SiH, 15.0 equiv. of BF3´Et2O,
MeCN, 278 to 2158C, 2 h, 78%; 5i) from 43, 2.0 equiv. of BF3´Et2O,
CH3CN, 2308C, 30 min 548: 87%; 49: 12%); from 44 548: 87%; 49: 12%).
more, compound 46 was hydrogenated 5H2, Pd5OH)2/C) to a
1
previously reported compound.28b The H and 13C NMR
spectra of 47 clearly showed its meso-symmetry, all the
methine protons having an axial orientation. An explanation
of these results might involve the spirocycles 48 and 49
which can be isolated when the reductive process is inter-
rupted after 4±5 min of reaction at 2788C and inde-
pendently subjected to reduction to give 46 and 47 in
identical yield and relative proportions as given earlier for
43 or 44.
the NOE difference spectra of 46 were observed on Ha2/
H11a, H4a/H5a, H5a/H9a and H9a/Ha8. Coupling constants
between angular methines H4a/H11aˆ8.3 Hz and H5a/
H9aˆ4.0 Hz, were typical values for interaction between
antiperiplanar and synclinal oxymethines, respectively,
indicating a trans, syn, cis fusion for either rings. Further-
O-Methylation of hemiacetal 44 under the base conditions
reported by Mori26l 5THF, MeI/NaH) gave the methyl

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1929
diacetal 45, which was doubly reduced by SI-LA treatment
5CH2Cl2, Et3SiH/BF3´OEt2/CH3CN/275 to 2308C) to com-
pound 47 in 78% yield.
gave 55, which was further oxidized to afford the ketone 56
51:1 mixture). Base hydrolysis gave hydroxy-ketone 57 and
hemiacetal 58 that were separated by column chroma-
tography.
Finally, the earlier method was applied to the synthesis of
tetracyclic compound 60 as an advanced model system for
this convergent approach 5Scheme 4). Generation of the
O-Methylation of the hemiacetal 58 following the earlier
described conditions gave the methyl diacetal 59, which
was reduced to compound 60 in 57% yield.27f Then, we
envisioned the reductive etheri®cation of hydroxy-ketone
57 and hemiacetal 58 to fused oxepane systems. Reduction
of 57 and 58 with Et3SiH in the presence of BF3´OEt2
resulted in the formation of diols 63 and 64 in the relative
proportions of 56:1), respectively. In order to check the
²
lithium acetylide of 50, followed by condensation with
lactone 51, yielded an inseparable mixture 51:1 ratio) of
³
diastereoisomers 52. Subsequent treatment with CSA/
MeOH gave, with loss of TBS group, a 1:1 mixture of
methyl acetals 53, which was further acetylated to give 54
51:1 mixture). Partial hydrogenation 510% Pd±BaSO4, H2)
Reagents and conditions: 5a) TBSCl 50.3 equiv.), CH2Cl2, 64%; 5b) SO3´py complex 53.0 equiv.), Et3N 57.0 equiv.), DMSO/CH2Cl2 51:1), 3 h, 98%;
5c) Ph3PvCHCO2Me 51.2 equiv.), NaH 51.0 equiv.), benzene, 1 h, 95%; 5d) DIBALH 52.0 equiv.), THF, 2 h, 82%; 5e) 2DET 50.12 equiv.) 5iPro)4Ti
50.1 equiv.), BuOOH 51.8 equiv.), CH2Cl2, 3 h, 90%; 5f) NMO 51.5 equiv.), TPAP catalyst, CH2Cl2, 91%; 5g) PPh3 54.0 equiv.), Br4C 52.0 equiv.), Et3N
t
51.0 equiv.), CH2Cl2, 78%; 5h) TBAF 51.5 equiv.), THF, 3 h, 98%; 5i) CSA catalyst, CH2Cl2, 0±258C, 93%; 5j) TMSCl 51.5 equiv.), imidazole 51.5 equiv.),
CH2Cl2, 96%.
Reagents and conditions: 5a) n-BuLi 52.0 equiv.), 2788C, THF, 30 min, then H2O, 81%; 5b) 5Sia)2BH 52.0 equiv.), THF, 08C, 12 h, then 3N NaOH
510.0 equiv.), 30% H2O2 520.0 equiv.), 08C, 2 h, 88%; 5c) NaH 51.3 equiv.), 5MeO)2POCH2CO2Me 51.2 equiv.), benzene, 258C, 15 min, 88%; 5d) DIBALH
t
Ê
55.0 equiv.), Et2O, 08C, 1.5 h; quench with NaOH±H2O, 98%; 5e) 51)DET 50.4 equiv.), BuOOH 51.8 equiv.), 4 A MS, CH2Cl2, 2208C, 12 h, 95%; 5f) TosCl
51.1 equiv.), 4-DAMP 50.05 equiv.), Et3N 52.5 equiv.), CH2Cl2, 258C, 8 h, 93%; 5g) NaI 52.3 equiv.), NaHCO3 52.0 equiv.), butanone, 608C, 1 h, 97%; 5h) tBuLi
52.0 equiv.), Et2O, 2788C, 2 h, 99%; 5i) BnCl 52.0 equiv.), 5iPr)2EtN 54.0 equiv.), 4-DAMP 50.1 equiv.), CH2Cl2, 258C, 6 h, 96%, 5ii) NMO 53.0 equiv.), OsO4
catalyst, THF/H2O/acetone 51:1:1), 258C, 12 h, 75%, 5iii) TBAF 51.2 equiv.), THF, 258C, 6 h, 5iv) 5n-Bu)4NIO4 52.5 equiv.), MeOH/H2O 54:1), 208C, 3 h, 81%
for two steps; 5j) PCC 51.5 equiv.) NaOAc 50.2 equiv.), CH2Cl2, 258C, 6 h, 73%.
²
³
Dibromoole®n 50, [a]D ˆ19.28 5c 2.08, CHCl3), was readily prepared as illustrated following a standard methodology.31
25
Lactone 51, [a]D ˆ21228 5c 1.77, CHCl3), was prepared starting from the dibromoole®n 32 following the synthetic sequence outlined.32
25

1930
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
compounds 11 and 29 51 nM±1 mM), were tested on the
isolated uterus, showing no induction of any signi®cant
contractile effect on myometrial preparations under resting
tone. It has been shown that some brevetoxin derivatives act
as Na1 channel antagonists,6d therefore, we analyzed the
possible inhibitory effects of a high concentration 51 mM)
of each of the selected polyethers on rhythmic contractions
elicited by BTX-2 530 nM). The compounds assayed
inhibited neither the frequency nor the amplitude of con-
tractions elicited by BTX-2, which revealed no binding to
the BTX-2 receptor site. In these same experiments,
addition of TTX 50.1 mM) caused the abolition of rhythmic
contractions. These data demonstrate that compounds 11 and
29 are also devoid of antagonist activity on Na1 channels.
3.1. Biological assays
All experiments were conducted in accordance with NIH
guidelines for the care and use of laboratory animals.
Uterine horns from virgin rats in the oestrous stage of the
hormonal cycle were removed and carefully cleaned.
mRNA expression of voltage-gated Na1 channels was
analyzed by reverse transcription-polymerase chain reaction
5RT-PCR). Total RNA from uterine tissue was isolated,
treated with DNase I and reverse-transcribed as previously
described.33 First strand cDNA was obtained and ampli®ed
by PCRusing speci®c oligonucleotide primers designed
from the sequences of rat Na1 channel subtypes.
Glyceraldehyde 3-phosphate dehydrogenase and b-actin
were used as housekeeping genes. Functional studies were
performed on isolated strips of rat uterine smooth muscle,
essentially as described.34 Strips of longitudinal smooth
muscle were prepared and mounted in tissue baths con-
taining 4 mL of Krebs solution of the following composition
5mM): NaCl 118; KCl 5.6; CaCl2 1.1; MgSO4 0.95;
NaHPO4 1.0; NaHCO3 25 and glucose 11. A physiological
solution with a low concentration of Ca21 was used to avoid
development of myometrial spontaneous contractions.35
Uterine strips were suspended under an initial tension of
0.5 g, gassed with 95% O2/5% CO2 and maintained at
378C. Mechanical responses were recorded isometrically
by means of force-displacement transducers 5Grass FT-
03). Preparations were allowed to equilibrate for a 60 min
period before addition of cumulative concentrations of
compounds 11 and 29 51 nM±1 mM) or of the selective
Na1 channel activator brevetoxin B 5BTX-2, 0.1 nM±
0.1 mM). Only one product was tested on each tissue.
When rhythmic contractions appeared, the selective Na1
channel blocker tetrodotoxin 5TTX, 0.1 mM) was added to
the bath in the continuous presence of the analyzed
compound. In another set of experiments, the response to
BTX-2 530 nM) was studied in the presence of a single
concentration 51 mM) of compounds 11 and 29, which
were added to the bath 20 min before BTX-2 and main-
tained in contact with the tissue during exposure to
BTX-2. Only one compound was tested in each strip.
Contractile responses were measured as peak increases in
force and expressed in mN.
Figure 7. Typical tracing showing the rhythmic contractions elicited by
brevetoxin B 5BTX-2, 30 nM) in isolated uterine strips from non-pregnant
rats. The rhythmic contractions were abolished by TTX 50.1 mM). The
record is representative of typical results in ®ve different animals.
intermediacy of spiroketones 61 and 62 in this unexpected
reductive process, compounds 57 and 58 were inde-
pendently treated with BF3´OEt2/MeCN to give, in a 1:1
ratio, spiroketones 61 and 62, which were separated and
their con®gurations at the spiroketal carbon determined by
1
2D COSY and 1D HNOE difference experiments. Reduc-
tion of 61 or 62 using BF3´Et2O and a large excess of Et3SiH
gave diols 63 and 64, as the only compounds to be isolated.
Unexpectedly, in compounds 61 and 62, the SI-LA induced
reduction of carbonyl group occurred prior to the dioxa-
spirocyclic functionality to give the hydroxy derivatives
65 and 66, which precluded the reductive etheri®cation
coupling to oxepene rings.
3. Biological studies
RT-PCR was used to investigate Na1 channel subtypes
mRNA expression in the rat uterus. As shown in Fig. 1,
six of the 10 voltage-gated Na1 channels cloned in the rat
are expressed in the uterus. The high-af®nity and selective
Na1 channel activator brevetoxin-B 5BTX-2, $30 nM)
caused the development of rhythmic contractions in isolated
strips of rat myometrium 5Fig. 7). The contractions were
rapidly and completely abolished by tetrodotoxin 5TTX,
0.1 mM). These data provide evidence that functionally
active voltage-gated Na1 channels exist in the non-pregnant
rat uterus.
4. Conclusions
Although none of the polyethers synthesized in this work
Ê
reach the required size 5,30 A long), some of them, i.e.
Model structures of several ciguatoxins indicated that these

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1931
Ê
molecules are ,30 A long and mostly ¯at, with a hinge part
Schlenk techniques. All other reagents were purchased
from Aldrich and used without further puri®cation unless
otherwise stated. All reactions were conducted in ¯ame-
dried glassware under an inert atmosphere of dry argon.
Tetrahydrofuran 5THF) and diethyl ether 5Et2O) were
distilled from sodium/benzophenone, dichloromethane
5CH2Cl2), acetonitrile 5MeCN), triethylamine 5Et3N), diiso-
propylamine, pyridine, benzene and toluene from calcium
hydride, dimethylsulfoxide 5DMSO) and N,N-dimethyl-
formamide 5DMF) from calcium hydride under reduced
pressure.
around the middle of the molecule and a large semi-rigid
curvature at one of the ends. From the results achieved here,
we can conclude that a similar mono-conformational situa-
tion can be reached by exclusive participation of oxane and
oxepane rings. trans-Fused polyethers with an odd number
of oxepane rings ¯anked by oxanes at both ends 5i.e. 11
or 29) present a `folded' shape conformation. The small
number of minima characterized for the compounds
investigated indicates that they are quite rigid. Accordingly,
the conformational preference can be explained by one-state
rather than a two-state equilibrium like in polycyclic
oxepane systems 5i.e. 4). However, an even number of
oxepanes ¯anked by oxanes in both ends 5i.e. 13 or 14)
introduces drastic changes in the pseudorotational
preferences given to highly ¯exible structures.
5.2. General procedure for O-alkylation
In a typical experimental procedure, the corresponding alco-
hol 50.3 mmol) was dissolved in dry THF 53.0 mL) and allyl
bromide 50.45 mmol) and a catalytic amount of n-Bu4NI
was added. The reaction mixture was cooled to 08C and
NaH 50.36 mm, 1.2 equiv., 60% dispersion in mineral oil)
was added and left overnight, allowing the temperature to
rise. The reaction mixture was cooled again to 08C and
water 52 mL) was added. The aqueous layer was extracted
with EtOAc 53£3 mL), combined organic layers were
washed with brine and dried over MgSO4. Solvent was
removed in vacuo and the residue was puri®ed by ¯ash
chromatography.
Convergent approaches to series of ortho-condensed
systems, via intermolecular coupling of polycyclic
segments can be used for the syntheses of oxane/oxepane
models with controlled size and conformational mobility.
Input from biological studies should provide additional
guiding principles.
5. Experimental
5.1. General experimental procedures
5.2.1. meso-12R,3S,6R,7S)-3,6-Bis-allyloxy-2,7-divinyl-
oxepane 11). Colorless oil; Rfˆ0.72 5hexane/EtOAc, 4:1);
1H NMRspectra were recorded on Bruker spectrometers
Avance DPX300 5300 MHz), Avance DRX400 5400 MHz)
or Avance DRX500 5500 MHz). Chemical shifts are
reported in parts per million from TMS with the solvent
resonance as the internal standard. Data are reported as
follows: chemical shift multiplicity 5sˆsinglet, dˆdoublet,
tˆtriplet, qˆquartet, brˆbroad, mˆmultiplet), integration,
coupling constants 5Hz) and assignment. 13C NMRspectra
were recorded Bruker on spectrometers Avance DPX300
575 MHz), Avance DRX400 5100 MHz) or Avance
DRX500 5125 MHz) with complete proton decoupling.
Chemical shifts are reported in parts per million from
TMS with the solvent as the internal reference. IRspectra
were recorded on a Bruker Vector 22 spectrosphotometer.
High resolution mass spectra were provided by the
Universities of Seville and Cordoba Mass Spectrometry
Facilities and were performed on Kratos MS80RFA,
Finnigan MAT 95 or Micromass AutoSpec Q spectrometers.
Melting points were determined on a Buchi 241 melting
points apparatus and are uncorrected. Optical rotations
were measured on a Perkin Elmer 341 polarimeter, using
the sodium D line at 258C. TLC was performed using Merck
silica gel 60F254 precoated plates 50.25 mm thickness) with
a ¯uorescent indictor, visualization was accomplished
with one or more of the following: UV light 5254 nm),
10% ethanolic phosphomolybdic acid or H2O/H2SO4/
AcOH 51:4:20) solution and heat as a developing agent.
Column chromatography was performed using Merck silica
gel 60 570±230 mesh) and, for ¯ash chromatography, Merck
silica gel 60 5234±400 mesh) was used. All chromato-
graphic separations were monitored by TLC analyses.
Bis5tricyclohexylphosphine)benzylideneruthenium5IV)
dichloride was purchased from Strem Chemicals, stored in a
dry-box and used under argon atmosphere with standard
1
IR5neat) 3693, 3012, 1726, 1640, 1220, 1084 cm 21; H
0
NMR5500 MHz, CDCl ) d 5.92±5.81 5m, 2H, H1 , H2 ),
00
3
00
5.30 5ddd, Jˆ17.5, 2.0, 2.0 Hz, 1H, H3 ), 5.25 5ddd, Jˆ
0
17.2, 3.5, 2.0 Hz, 1H, H2 ), 5.14 5ddd, Jˆ10.5, 3.5, 2.0 Hz,
00
0
1H, H3 ), 5.06 5ddd, Jˆ10.6, 2.0, 2.0 Hz, 1H, H2 ), 4.02
00
5dddd, Jˆ12.5, 5.5, 2.0, 2.0 Hz, 1H, H1 ), 4.01 5dddd, Jˆ
11.4, 6.4, 2.0, 2.0 Hz, 1H, H2), 3.83 5ddd, Jˆ5.5, 2.0,
00
2.0 Hz, 1H, H1 ), 3.42 5ddd, Jˆ6.4, 5.0, 4.0 Hz, 1H, H3),
1.88±1.81 5m, 1H, H4), 176±1.68 5m, 1H, H4); 13C NMR
0
5125 MHz, CDCl3) d 137.6 5d, C1 ), 135.4 5d, C2 ), 117.0 5t,
00
00
0
00
C3 ), 114.5 5t, C2 ), 83.9 5d, C2), 81.4 5d, C3), 69.9 5t, C1 ),
24.2 5t, C4); HRMS Calcd for C16H24O3 5M1): 264.17253;
Found: 264.17261.
5.2.2.
meso-12R,3S,6R,7S)-2,6-Diallyl-3,6-bis-allyloxy-
oxepane 12). Colorless oil; Rfˆ0.42 5hexane/EtOAc, 2:1);
1
IR5neat) 3014, 1726, 1640, 1410, 1230, 1090 cm 21; H
NMR5500 MHz, CDCl ) d 5.88 5dddd, Jˆ17.2, 10.2, 5.7,
3
00
5.3 Hz, 1H, H2 ), 5.85 5dddd, Jˆ17.2, 10.2, 8.0, 7.0 Hz, 1H,
0
00
H2 ), 5.23 5d, Jˆ17.2 Hz, 1H, H3 ), 5.13 5d, Jˆ10.2 Hz, 1H,
00
0
H3 ), 5.05 5d, Jˆ17.2 Hz, 1H, H3 ), 5.02 5d, Jˆ10.2 Hz, 1H,
0
00
H3 ), 4.03 5brdd, Jˆ12.5, 5.3 Hz, 1H, H1 ), 3.83 5brdd,
00
Jˆ12.5, 5.7 Hz, 1H, H1 ), 3.31 5brddd, Jˆ8.2, 8.0, 3.2 Hz,
1H, H2), 3.22±3.16 5m, 1H, H3), 2.43 5brddd, Jˆ14.5, 8.0,
0
0
3.2 Hz, 1H, H1 ), 2.16 5ddd, Jˆ14.5, 8.0, 7.2 Hz, 1H, H1 ),
1.83±1.76 5m, 1H, H4), 1.75±1.67 5m, 1H, H4); 13C NMR
00
5125 MHz, CDCl3) d 135.9 5d, C2 ), 135.0 5d, C2 ), 117.1 5t,
0
00
0
C3 ), 116.8 5t, C3 ), 84.7 5d, C2), 82.2 5d, C3), 70.1 5t, C1 ),
00
1
38.9 5t, C1 ), 24.5 5t, C4); HRMS Calcd for C18H28O3 5M ):
292. 20383; Found: 292.20379.
0
5.2.3. meso-12R,3S,6R,7S)-Bis-allyloxy-2,7-di-but-30-enyl-
oxepane 13). Colorless oil; Rfˆ0.43 5hexane/EtOAc, 2:1);
1
IR5neat) 3693, 3011, 1726, 1640, 1420, 1084 cm 21; H

1932
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
0
NMR5500 MHz, CDCl ) d 5.86 5dddd, Jˆ17.2, 10.4, 5.8,
5dddd, Jˆ12.7, 5.4, 1.5, 1.5 Hz, 1H, H1 ), 3.99 5dddd,
3
00
5.6 Hz, 1H, H2 ), 5.83 5dddd, Jˆ17.1, 10.1, 8.0, 5.0 Hz, 1H,
Jˆ11.2, 5.2, 1.7, 1.7 Hz, 1H, H6), 3.85 5ddd, Jˆ5.7, 1.4,
0
00
0
H3 ), 5.23 5brd, Jˆ17.2 Hz, 1H, H3 ), 5.12 5brd, Jˆ10.4 Hz,
1.4 Hz, 1H, H2), 3.82 5ddd, Jˆ5.7, 1.6, 1.6 Hz, 1H, H1 ),
00
0
1H, H3 ), 5.00 5brd, Jˆ17.1 Hz, 1H, H4 ), 4.93 5brd, Jˆ
3.43 5ddd, Jˆ4.9, 4.9, 2.9 Hz, 1H, H7), 3.28 5brdddd, Jˆ
14.8, 11.3, 9.0, 6.2 Hz, 1H, H2), 3.23 5ddd, Jˆ11.1, 9.2,
4.6 Hz, 1H, H4a), 2.98 5brddd, Jˆ9.3, 9.2, 5.2 Hz, 1H,
H9a), 2.05 5dddd, Jˆ12.8, 6.6, 4.6, 3.6 Hz, 1H, H4), 1.93
5brddd, Jˆ13.4, 9.0, 4.5 Hz, 1H, H8), 1.84±1.73 5m, 2H,
2£H9), 1.69±1.60 5m, 3H, 2£H3, H8), 1.43 5brdd, Jˆ12.4,
11.1, 7.0 Hz, 1H, H4); 13C NMR5125 MHz, CDCl 3) d 137.9
0
00
10.1 Hz, 1H, H4 ), 4.04 5brdd, Jˆ12.6, 5.5 Hz, 1H, H1 ),
00
3.84 5brdd, Jˆ12.6, 5.8 Hz, 1H, H1 ), 3.27 5ddd, Jˆ9.5,
8.0, 3.2 Hz, 1H, H2), 3.15 5brddd, Jˆ8.0, 7.5, 3.5 Hz, 1H,
0
H3), 2.28 5brdddd, Jˆ14.2, 8.0, 4.8, 2.0 Hz, 1H, H2 ), 2.10
0
5brdddd, Jˆ14.2, 11.0, 5.0, 3.0 Hz, 1H, H2 ), 1.83 5brdddd,
0
Jˆ14.3, 11.0, 4.8, 3.0 Hz, 1H, H1 ), 1.81±1.74 5m, 1H, H4),
13
0
5d, C2 ), 134.8 5d, C1 ), 116.8 5t, C3 ), 114.5 5t, C2 ), 83.9 5d,
0
C6), 82.7 5d, C9a), 81.3 5d, C7), 80.5 5d, C4a), 69.9 5t, C1 ),
00
0
00
1.73±1.66 5m, 1H, H4), 1.46 5dddd, Jˆ14.3, 9.5, 5.0, 4.8 Hz,
0
1H, H1 ); C NMR5125 MHz, CDCl ) d 139.0 5d, C3 ),
0
3
00
00
0
135.7 5d, C2 ), 117.0 5t, C3 ), 114.4 5t, C4 ), 84.0 5d, C2),
67.6 5t, C2), 31.4 5t, C4), 26.9 5t, C9), 27.5 5t, C3), 23.8 5t, C8);
HRMS Calcd for C14H22O3 5M1): 238.99491; Found:
238.99468.
00
0
0
82.5 5d, C3), 70.2 5t, C1 ), 34.3 5t, C1 ), 30.7 5t, C2 ), 24.6 5t,
C4); HRMS Calcd for C20H32O3 5M1): 320.23513; Found:
320.23547.
5.2.6. 14aS,5aR,8S,9R,10aS,12aR)-8-Allyloxy-9-vinyl-
dodecahydro-1,5,10-trioxa-benzo[b]heptalene 16). Color-
5.2.4. meso-12R,3S,5aR,6aS,9R,10S,11aR,13aS)-3,9-Bis-
allyloxy-2,10-divinyl-tetradecahydro-1,6,11-trioxa-cyclo-
hepta[1,2-b]-heptalene 14). Colorless oil; Rfˆ0.65 5hexane/
EtOAc, 4:1); IR5neat) 3693, 3011, 2360, 1726, 1220,
25
less oil; Rfˆ0.91 5hexane/EtOAc, 13:7); [a]D ˆ124.48 5c
0.43, CHCl3); IR5neat) 3008, 1162, 1378, 1087, 763 cm 21
;
1H NMR5500 MHz, CDCl ) d 5.86 5dddd, Jˆ17.3, 10.4,
3
1084 cm21
;
1H NMR5500 MHz, CDCl 3) d 5.85 5ddd,
5.7, 5.7 Hz, 1H, H2 ), 5.79 5ddd, Jˆ17.2, 10.5, 5.3 Hz, 1H,
0
0
00
00
Jˆ17.2, 10.6, 4.7 Hz, 1H, H1 ), 5.80 5dddd, Jˆ17.2, 10.5,
H1 ), 5.28 5ddd, Jˆ17.2, 1.8, 1.8 Hz, 1H, H2 ), 5.24 5ddd,
00
0
5.3, 5.3 Hz, 1H, H2 ), 5.47 5ddd, Jˆ17.2, 2.0, 2.0 Hz, 1H,
Jˆ17.2, 1.7, 1.7 Hz, 1H, H3 ), 5.12 5dddd, Jˆ10.4, 1.5,
0
00
0
H2 ), 5.21 5ddd, Jˆ17.2, 3.4, 1.8 Hz, 1H, H3 ), 5.08 5ddd,
1.5 Hz, 1H, H3 ), 5.07 5dddd, Jˆ10.5, 1.7, 1.7 Hz, 1H,
0
00
Jˆ10.6, 2.0, 1.9 Hz, 1H, H2 ), 5.02 5ddd, Jˆ10.5, 3.4,
H2 ), 4.04 5dddd, Jˆ5.4, 3.7, 1.8, 1.8 Hz, 1H, H9), 4.00
00
1.6 Hz, 1H, H3 ), 4.23 5ddd, Jˆ8.2, 5.3, 1.9 Hz, 1H, H2),
5dddd, Jˆ12.7, 5.3, 1.5, 1.5 Hz, 1H, H1), 3.86±3.81 5m,
00
0
3.78 5dddd, Jˆ12.9, 5.3, 1.7, 1.6 Hz, 1H, H1 ), 3.71 5ddd,
2H, H1 , H2), 3.66 5ddd, Jˆ9.0, 5.4, 5.3 Hz, 1H, H10a),
Jˆ9.1, 6.9, 4.9 Hz, 1H, H11a), 3.62 5dddd, Jˆ12.9, 5.3, 1.6,
3.43 5ddd, Jˆ6.1, 3.7, 2.0 Hz, 1H, H8), 3.35 5brdd, Jˆ
14.6, 4.6 Hz, 1H, H5a), 3.27 5ddd, Jˆ9.1, 6.8, 6.8 Hz, 1H,
H12a), 3.14 5ddd, Jˆ11.5, 9.1, 4.0 Hz, 1H, H4a), 2.95 5ddd,
Jˆ9.1, 6.8, 6.8 Hz, 1H, H12a), 2.03 5brdd, Jˆ12.1, 3.9 Hz,
1H, H4), 1.98±1.86 5m, 2H, 2£H11), 1.86±1.77 5m, 5H,
2£H12, H7, 2£H6), 1.67±1.58 5m, 3H, 2£H3, H7), 1.41
5brdd, Jˆ12.1, 11.5 Hz, 1H, H4); 13C NMR5125 MHz,
00
1.6 Hz, 1H, H1 ), 3.39 5ddd, Jˆ8.2, 6.3, 2.2 Hz, 1H, H3),
3.37 5brddd, Jˆ10.4, 9.1, 4.7 Hz, 1H, H5a), 2.06 5dddd,
Jˆ15.6, 12.9, 10.4, 2.3 Hz, 1H, H5), 2.01 5brdd, Jˆ14.5,
6.9 Hz, 1H, H12), 1.89 5brddd, Jˆ15.9, 6.5, 4.7 Hz, 1H,
H5), 1.85 5brdd, Jˆ14.4, 4.9 Hz, 1H, H12), 1.72 5brddd,
Jˆ14.7, 6.5, 6.3 Hz, 1H, H4), 1.59 5brdd, Jˆ14.7,
12.5 Hz, 1H, H4); 13C NMR5125 MHz, CDCl ) d 138.4
CDCl3) d 137.8 5d, C2 ), 134.9 5d, C1 ), 116.7 5t, C3 ),
0
00
0
3
0
00
00
0
5d, C1 ), 135.2 5d, C2 ), 115.7 5t, C3 ), 113.9 5t, C2 ), 85.6
00
114.8 5t, C2 ), 84.4 5d, C5a), 83.3 5d, C12a), 83.2 5d, C9),
0
82.3 5d, C4a), 82.0 5t, C10a), 81.5 5d, C8), 69.8 5t, C1 ), 67.9
5d, C5a), 82.9 5d, C2), 82.4 5d, C11a), 81.7 5d, C3), 69.5 5t,
00
1
C1 ), 29.9 5t, C12), 28.2 5t, C5), 22.8 5t, C4); H NMR
5t, C2), 31.6 5t, C4), 30.7 5t, C11), 28.9 5t, C12), 27.9 5t, C6),
26.1 5t, C3), 23.1 5t, C7); HRMS Calcd for C18H28O4 5M1):
308.19876; Found: 308.19883.
5500 MHz, C6D6) d 5.87 5dddd, Jˆ17.2, 10.5, 5.6, 5.3 Hz,
00
0
1H, H2 ), 5.78 5ddd, Jˆ17.2, 10.6, 5.2 Hz, 1H, H1 ), 5.28
0
5ddd, Jˆ17.2, 2.0, 2.0 Hz, 1H, H2 ), 5.23 5dddd, Jˆ17.2, 2.0,
00
2.0, 2.0 Hz, 1H, H3 ), 5.13 5ddd, Jˆ10.5, 2.0, 2.0 Hz, 1H,
5.2.7. 14aR,5aS,8R,9S,10aR,12aS)-8-Allyloxy-2,2-dimethyl-
9-vinyl-decahydro-1,3,5,10-tetraoxabenzo[b]heptalene 17).
00
0
H3 ), 5.07 5ddd, Jˆ10.6, 2.0, 2.0 Hz, 1H, H2 ), 4.07 5ddd,
25
Jˆ8.0, 5.3, 2.0 Hz, 1H, H2), 3.99 5dddd, Jˆ12.7, 5.6, 2.0,
Colorless foam; Rfˆ0.48 5hexane/EtOAc, 4:1); [a]D
1455, 1011, 876 cm21
ˆ
00
2.0 Hz, 1H, H1 ), 3.83 5dddd, Jˆ12.2, 5.3, 2.0, 2.0 Hz, 1H,
226.68 5c 0.35, CHCl3); IR5KBr) 3017, 2933, 1601,
;
00
H1 ), 3.58±3.54 5m, 1H, H5a), 3.47 5ddd, Jˆ6.0, 4.0, 2.0 Hz,
1H NMR5500 MHz, CDCl 3) d
0
00
1H, H3), 3.29 5brddd, Jˆ15.3, 15.3, 9.0 Hz, 1H, H11a),
1.90±1.82 5m, 3H, H4, 2£H5), 1.81±1.75 5m, 2H, 2£H12),
1.61±1.52 5m, 1H, H4); 13C NMR5125 MHz, C 6D6) d 137.8
5.91±5.80 5m, 2H, H2 , H1 ), 5.28 5ddd, Jˆ17.8, 1.7,
00
0
1.7 Hz, 1H, H2 ), 5.24 5dd, Jˆ17.7, 1.7 Hz, 1H, H3 ), 5.15
0
5dd, Jˆ10.4, 1.5 Hz, 1H, H3 ), 5.08 5ddd, Jˆ10.6, 1.7,
00
0
0
00
5d, C2 ), 134.8 5d, C1 ), 116.7 5t, C2 ), 114.7 5t, C3 ), 85.7 5d,
00
0
1.7 Hz, 1H, H2 ), 4.03±3.96 5m, 3H, H4, H9, H1 ), 3.90±
00
C5a), 83.0 5d, C2), 82.3 5d, C11a), 81.9 5d, C3), 69.7 5t, C1 ),
29.7 5t, C12), 27.9 5t, C5), 22.8 5t, C4); HRMS Calcd for
C24H36O5 5M1): 404.25628; Found: 404.25514.
0
3.82 5m, 3H, H4, H4a, H1 ), 3.47 5brdd, Jˆ7.6, 4.7 Hz, 1H,
H8), 3.24±3.18 5m, 2H, H10a, H12a), 3.04 5ddd, Jˆ10.0, 10.0,
5.0 Hz, 1H, H5a), 2.08 5brdddd, Jˆ12.7, 4.5, 4.5, 4.0 Hz, 1H,
H11), 1.94±1.89 5m, 2H, H7, H12), 1.79 5brdddd, Jˆ12.3,
11.8, 10.5, 10.5 Hz, 1H, H6), 1.76±1.71 5m, 1H, H6), 1.62
5dddd, Jˆ13.4, 12.7, 2.4, 2.4 Hz, 1H, H7), 1.46 5dddd, Jˆ
13.4, 12.7, 12.5, 4.0 Hz, 1H, H11), 1.38 5s. 3H, CH3-2),
1.36±1.33 5m, 1H, H12), 1.32 5s, 3H, CH3-2); 13C NMR
5.2.5. 14aS,6R,7S,9aR)-7-Allyloxy-6-vinyl-octahydro-1,5-
dioxa-benzocycloheptene 15). Colorless oil; Rfˆ0.57
25
5hexane/EtOAc, 7:3); [a]D ˆ124.08 5c 0.31, CHCl3); IR
1
5neat) 3685, 3013, 1731, 1602, 1232, 738 cm21; H NMR
0
5500 MHz, CDCl3) d 5.91±5.80 5m, 2H, H2 , H1 ), 5.28
00
00 0
5125 MHz, CDCl3) d 138.2 5d, C1 ), 135.3 5d, C2 ), 117.2
0
0
00
5ddd, Jˆ17.3, 1.8, 1.8 Hz, 1H, H3 ), 5.24 5ddd, Jˆ17.3,
5t, C3 ), 115.0 5t, C2 ), 109.7 5s, C2), 84.3 5d, C9), 82.8 5d,
C5a), 81.7 5d, C8), 80.8 5d, C10a), 78.5 5d, C12a), 78.3 5d, C4a),
00
3.5, 5.3, 1.8 Hz, 1H, H2 ), 5.13 5ddd, Jˆ10.4, 3.1, 1.5 Hz,
0
00
0
70.3 5t, C1 ), 67.7 5t, C4), 31.2 5t, C11), 28.1 5t, C12), 27.2
1H, H3 ), 5.07 5ddd, Jˆ10.6, 1.8, 1.7 Hz, 1H, H2 ), 4.02

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1933
5t, C6), 27.1 5q, CH3-2), 25.7 5q, CH3-2), 24.2 5t, C7);
HRMS Calcd for C19H30O5 5M1): 338.20930; Found:
338.20936.
4,5,5a,6a,7,8,9,10,11a,12,13,13a-tetradecahydro-1,6,11-
trioxa-cyclohepta[b]heptalene 590). Colorless oil; Rfˆ0.81
5hexane/EtOAc, 4:1); IR5neat) 3002, 2940, 1726, 1610,
1234, 920 cm21 1H NMR5500 MHz, CDCl 3) d 3.73
;
5ddd, Jˆ12.0, 8.8, 6.0 Hz, 1H, H2), 3.66 5ddd, Jˆ12.0,
10.5, 4.8 Hz, 1H, H2), 3.30 5ddd, Jˆ14.0, 9.0, 4.8 Hz, 1H,
H5a), 3.27 5brs, 1H, H11a), 2.08±2.03 5m, 1H, H5), 1.85±1.81
5m, 2H, 2£H12), 1.75±1.70 5m, 1H, H4), 1.67±1.60 5m, 2H,
5.3. General procedure for ole®n metathesis
The amount of catalyst necessary in each case was weighted
and dissolved in dry CH2Cl2 in a ¯ame-dried vessel 510±
30 mol% of catalyst). A solution of the corresponding diene
in CH2Cl2 was then added dropwise via cannula to the above
solution under an atmosphere of dried argon 5®nal concen-
tration of diene 6£1023 M). When addition ®nished, the
vessel was sealed and the reaction mixture was stirred at
room temperature 52±4 h). Progress of reaction was tested
by TLC and NMR. When the reaction ®nished or when no
further progress was observed, solvent was removed in
vacuo and the residue was puri®ed by ¯ash chromatography,
affording the expected unsaturated heterocycle.
H3, H4), 1.54±1.46 5m, 1H, H3), 1.42±1.37 5m, 1H, H5); 13
C
NMR5125 MHz, CDCl 3) d 86.4 5d, C11a), 80.9 5d, C5a), 68.9
5t, C2), 36.0 5d, C5), 29.3 5t, C12), 28.7 5t, C4), 20.9 5t, C3);
HRMS Calcd for C14H24O3 5M1): 240.17253; Found:
240.17338.
5.3.3.
meso-11S,3R,10S,13R)-2,9,14-Trioxa-tricyclo-
[11.6.0.03,10]nonadeca-6,16-diene 110). Colorless oil; Rfˆ
0.68 5hexane/EtOAc, 4:1); IR5neat) 3017, 2940, 2341,
1724, 1610, 1422, 1284, 980 cm21; H NMR5500 MHz,
1
CDCl3) d 5.68 5ddd, Jˆ11.0, 2.0, 2.0 Hz, 1H, H3), 5.72
5brddd, Jˆ9.7, 9.4, 8.3 Hz, 1H, H6), 5.26 5brddd, Jˆ9.7,
3.0, 2.0 Hz, 1H, H7), 4.37 5brd, Jˆ6.8 Hz, 1H, H8), 4.01
5brdd, Jˆ6.8, 3.0 Hz, 1H, H8), 3.48 5brs, 1H, H1), 3.39
5ddd, Jˆ10.7, 10.0, 5.0 Hz, 1H, H10), 2.57 5brddd, Jˆ
11.4, 10.8, 9.5 Hz, 1H, H5), 2.06 5brddd, Jˆ11.4, 9.3,
9.2 Hz, 1H, H5), 2.02±1.96 5m, 1H, H4), 1.83±1.78 5m,
1H, H11), 1.74±1.68 5m, 1H, H11), 1.45 5brddd, Jˆ12.0,
5.3.1. meso-12R,3S,6R,7S)-2,4a,5a,8,9a,10,11,11a-Octa-
hydro-1,5,9-trioxa-dibenzo[a,d]cycloheptane 18). Color-
less oil; Rfˆ0.71 5hexane/EtOAc, 4:1); IR5neat) 3017,
2941, 1610, 1460, 1220 cm21
;
1H NMR5500 MHz,
CDCl3) d 5.80 5ddd, Jˆ11.0, 4.5, 2.5 Hz, 1H, H4), 5.75
5ddd, Jˆ11.0, 2.0, 2.0 Hz, 1H, H3), 4.18 5ddd, Jˆ12.0,
4.5, 2.0 Hz, 1H, H2), 4.14 5ddd, Jˆ12.0, 2.5, 2.0 Hz, 1H,
H2), 4.01 5dd, Jˆ8.4, 2.0 Hz, 1H, H4a), 3.36 5ddd, Jˆ8.4,
7.8, 6.5 Hz, 1H, H9a), 1.95±1.88 5m, 2H, 2£H10); 13C NMR
5125 MHz, CDCl3) d 128.1 5d, C4), 128.0 5d, C3), 80.1 5d,
C9a), 75.7 5d, C4a), 65.7 5t, C2), 29.4 5t, C10); HRMS Calcd
for C12H16O3 5M1): 208.10993; Found: 208.10982. Com-
pound 8 was hydrogenated 510% Pd±C cat/H2/EtOAc/258
C/2 h) to give tetrahydro derivative: meso-24aR,5aS,9aS,
11aR)-2,3,4,4a,5a,6,7,8,9a,10,11,11a-dodecahydro-1,5,9-
trioxa[a,d]cycloheptane 580). Colorless oil; Rfˆ0.73 5hex-
11.4, 10.8 Hz, 1H, H4); 13C NMR5125 MHz, CDCl ) d
3
130.8 5d, C6), 127.0 5d, C7), 81.2 5d, C1), 84.2 5d, C10),
68.4 5t, C8), 34.1 5t, C4), 27.3 5t, C11), 23.1 5t, C5); HRMS
Calcd for C16H24O3 5M1): 264.17253; Found: 264.17354.
5.3.4.
meso-14aS,5aR,7aS,8aS,12aS,14aR,15aS,17aR)-
2,4a,5a,6,7,7a,8a,11,12a,13,14,14a,15a,16,17,17a-Hexa-
decahydro-1,5,8,12,15-pentaoxa-dibenzocyclohepten-
[6,7-a:60,70-e]cycloheptene 111). Colorless oil; Rfˆ0.23
5hexane/EtOAc, 4:1); IR5neat) 3017, 2941, 2341, 1726,
ane/EtOAc, 3:1); IR5neat) 3002, 2980, 1604, 1242, 1085,
1
1442, 1284, 1087 cm21; H NMR5500 MHz, CDCl ) d
1
960 cm21; H NMR5500 MHz, CDCl ) d 3.82 5ddd, Jˆ
3
3
5.75 5dddd, Jˆ10.3, 3.0, 1.6, 1.6 Hz, 1H, H4), 5.73 5ddd,
Jˆ10.3, 3.5, 1.9 Hz, 1H, H3), 4.12 5dddd, Jˆ16.7, 3.5, 2.1,
1.4 Hz, 1H, H2), 4.06 5dddd, Jˆ16.7, 2.6, 2.6, 1.4 Hz, 1H,
H2), 3.78 5ddd, Jˆ8.5, 3.0, 1.3 Hz, 1H, H4a), 3.40 5dddd,
Jˆ8.7, 5.3, 3.5, 1.8 Hz, 1H, H5a), 3.32 5ddd, Jˆ8.8, 8.7,
5.0 Hz, 1H, H14a), 3.22 5ddd, Jˆ9.2, 8.3, 4.6 Hz, 1H,
H12a), 2.08 5dddd, Jˆ13.0, 7.5, 5.0, 2.9 Hz, 1H, H13), 2.04
5dddd, Jˆ13.0, 7.5, 4.6, 4.6 Hz, 1H, H14), 1.92±1.88 5m, 2H,
2£H6), 1.80 5dddd, Jˆ13.0, 9.1, 7.8, 4.6 Hz, 1H, H13), 1.74
5dddd, Jˆ13.0, 9.0, 7.8, 2.9 Hz, 1H, H14); 13C NMR5125
MHz, CDCl3) d 127.9 5d, C4), 127.4 5d, C3), 85.7 5d, C14a),
83.6 5d, C5a), 77.2 5d, C4a), 77.1 5d, C12a), 65.7 5t, C2), 30.8 5t,
C14), 29.3 5t, C13), 29.2 5t, C6); HRMS Calcd for C20H28O5
5M1): 348.19367; Found: 348.19311. Anal. Calcd for
C20H28O5: C, 68.96; H, 8.04. Found: C, 68.93; H, 8.10.
11.5, 4.0, 2.0 Hz, 1H, H2), 3.24 5ddd, Jˆ11.5, 10.0,
4.5 Hz, 1H, H2), 3.22 5ddd, Jˆ9.0, 9.0, 4.5 Hz, 1H, H4a),
3.11 5ddd, Jˆ9.0, 8.5, 4.6 Hz, 1H, H9a), 2.10 5dddd, Jˆ11.5,
9.0, 4.0, 2.0 Hz, 1H, H4), 1.98±1.91 5m, 2H, 2£H11), 1.68±
1.62 5m, 2H, 2£H3), 1.45 5ddd, Jˆ12.5, 11.5, 6.0 Hz, 1H,
H4); 13C NMR5125 MHz, CDCl ) d 82.0 5d, C9a), 81.0 5d,
3
C4a), 67.8 5t, C2), 32.1 5t, C4), 30.6 5t, C10), 26.0 5t, C3);
HRMS Calcd for C12H20O3 5M1): 212.14123; Found:
212.14224.
5.3.2. meso-15aS,6aR,11aS,13aR)-2,5,5a,6a,7,10,11a,12,13,
13a-Decahydro-1,6,11-trioxa-cyclohepta[b]heptalene 19).
Colorless oil; Rfˆ0.72 5hexane/EtOAc, 4:1); IR5neat) 3018,
2940, 1726, 1610, 1220 cm21; 1H NMR5500 MHz, CDCl 3)
d 5.68 5ddd, Jˆ11.0, 2.0, 2.0 Hz, 1H, H3), 5.67 5ddd,
Jˆ11.0, 2.0, 2.0 Hz, 1H, H4), 4.20 5brdd, Jˆ14.5, 2.0 Hz,
1H, H2), 3.97 5brdd, Jˆ14.5, 2.0 Hz, 1H, H2), 3.38 5ddd,
Jˆ10.0, 8.0, 4.0 Hz, 1H, H5a), 3.29 5brddd, Jˆ8.0, 3.0,
3.0 Hz, 1H, H11a), 2.58 5ddd, Jˆ12.0, 4.0, 2.0 Hz, 1H, H5),
2.24 5dd, Jˆ12.0, 10.0 Hz, 1H, H5), 1.98±1.92 5m, 2H,
2£H12); 13C NMR5125 MHz, CDCl 3) d 130.2 5d, C3),
125.8 5d, C4), 86.0 5d, C11a), 83.5 5d, C5a), 68.4 5t, C2),
36.7 5t, C5), 29.3 5t, C12); HRMS Calcd for C14H20O3
5M1): 236.14123; Found: 236.14224. Compound 9 was
hydrogenated 510% Pd±C cat/H2/EtOAc/258C/2 h) to give
the tetrahydro derivative: meso-25aS,6aR,11aS,13aR)-2,3,
5.3.5. 14aS,6R,7S,9aR)-2,3,4,4a,5a,8,9a,10,11,11a-Deca-
hydro-1,5,9-trioxa-dibenzo[a,b]cycloheptene 112). Color-
25
less oil; Rfˆ0.41 5hexane/EtOAc, 3:1); [a]D ˆ1328 5c
0.22, CHCl3); IR5neat) 3696, 3016, 1727, 1600, 1443,
1
1088 cm21; H NMR5500 MHz, CDCl ) d 5.77 5ddd, Jˆ
3
10.4, 4.3, 2.8 Hz, 1H, H7), 5.74 5ddd, Jˆ10.4, 1.7, 1.7 Hz,
1H, H6), 4.11 5dd, Jˆ14.4, 2.8 Hz, 1H, H8), 4.10 5dd, Jˆ
14.4, 4.4 Hz, 1H, H8), 3.95 5dd, Jˆ8.6, 1.7 Hz, 1H, H5a),
3.83 5ddd, Jˆ11.3, 3.9, 1.8 Hz, 1H, H2), 3.33 5ddd, Jˆ8.6,
7.4, 7.0 Hz, 1H, H9a), 3.25 5ddd, Jˆ11.2, 7.3, 4.9 Hz, 1H,

1934
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
H2), 3.18 5ddd, Jˆ11.0, 8.8, 4.0 Hz, 1H, H4a), 3.03 5ddd,
Jˆ8.8, 8.4, 4.1 Hz, 1H, H11a), 2.14 5dddd, Jˆ14.3, 10.2, 7.0,
5.2 Hz, 1H, H10), 2.08 5dddd, Jˆ12.4, 8.1, 4.2, 1.7 Hz, 1H,
H4), 1.95 5dddd, Jˆ14.7, 6.3, 5.2, 4.1 Hz, 1H, H11), 1.88
5dddd, Jˆ14.7, 10.2, 5.0 Hz, 1H, H11), 1.79 5dddd, Jˆ
14.3, 7.4, 6.3, 5.0 Hz, 1H, H10), 1.67±1.61 5m, 2H, 2£H3),
1.43 5ddd, Jˆ12.5, 11.0, 5.8 Hz, 1H, H4); 13C NMR5125
MHz, CDCl3) d 127.9 5d, C6), 127.8 5d, C7), 81.7 5d, C11a),
80.9 5d, C4a), 77.8 5d, C9a), 75.3 5d, C5a), 67.7 5t, C2), 65.8 5t,
C8), 31.2 5t, C4), 30.4 5t, C11), 29.2 5t, C10), 25.8 5t, C3);
HRMS Calcd for C12H18O3 5M1): 210.12560; Found:
210.12581.
72.3 5d), 72.2 5t), 69.2 5d), 65.9 5t), 60.5 5t), 50.8 5q), 29.3 5t),
24.5 5t), 24.4 5t), 23.1 5t). Anal. Calcd for C20H26O5: C,
69.34; H, 7.56. Found: C, 69.29; H, 7.80.
5.3.9.
tetrahydropyran-200-yl)ethynyl]-tetrahydropyran-3-ol 136).
12R,3S,200S,300S)-2-[300-1Benzyloxy-200-methoxy-
25
Colorless oil; Rfˆ0.46 5hexane/EtOAc, 1:1); [a]D
ˆ
242.78 5c 0.8, CHCl3); IR5neat) 3604, 3019, 2867, 1464,
1117 cm21; H NMR5400 MHz, CDCl ) d 7.36±7.25 5m,
1
3
5H), 4.78 5d, Jˆ12.2 Hz, 1H), 4.66 5d, Jˆ12.2 Hz, 1H), 4.07
5d, Jˆ7.0 Hz, 1H), 3.94 5ddd, Jˆ11.8, 4.4, 4.4 Hz, 1H),
3.75±3.69 5m, 2H), 3.61 5ddd, Jˆ11.0, 7.0, 3.9 Hz, 1H),
3.49 5s, 3H), 3.44 5ddd, Jˆ11.8, 9.1, 2.4 Hz, 1H), 3.37
5dd, Jˆ7.8, 3.9 Hz, 1H), 3.09 5brs, 1H, D2O-exchangeable),
2.12±2.07 5m, 1H), 1.91±1.87 5m, 1H), 1.77±1.70 5m, 3H),
1.62±1.57 5m, 1H), 1.53±1.43 5m, 2H); 13C NMR5100
MHz, CDCl3) d 138.4 5s), 128.3 5d), 128.6 5d), 127.9 5d),
127.8 5d), 127.6 5d), 99.1 5s), 85.1 5s), 77.4 5d), 72.7 5d), 72.7
5t), 72.6 5d), 69.5 5d), 66.3 5t), 62.8 5t), 51.2 5q), 29.5 5t), 26.1
5t), 23.4 5q), 22.3 5t). Anal. Calcd for C20H26O5: C, 69.34; H,
7.56. Found: C, 69.17; H, 7.73.
5.3.6. 14aS,6aR,7aS,11aR,12aS,14aR)-2,3,4,4a,5a,6,7,7a,9,
11a,12a,13,14,14a-Tetrahydro-1,5,8,12-tetraoxa-dibenzo-
[b,h]heptalene 113). Colorless oil; Rfˆ0.42 5hexane/
25
EtOAc, 4:1); [a]D ˆ159.18 5c 0.81, CHCl3); IR5neat)
1
3696, 3012, 2930, 1726, 1463, 1211, 837, 686 cm21; H
NMR5500 MHz, CDCl 3) d 5.74 5s, 2H, H3, H4), 4.10
5brd, Jˆ15.7 Hz, 1H, H2), 4.07 5brd, Jˆ15.7 Hz, 1H, H2),
3.83 5dddd, Jˆ11.3, 5.1, 1.8, 1.8 Hz, 1H, H9), 3.74 5brdd,
Jˆ8.2, 2.9 Hz, 1H, H4a), 3.55 5ddd, Jˆ8.3, 4.8, 4.8 Hz, 1H,
H5a), 3.47 5ddd, Jˆ8.3, 8.3, 5.8 Hz, 1H, H12a), 3.26 5ddd,
Jˆ11.3, 9.4, 6.8 Hz, 1H, H9), 3.19 5ddd, Jˆ10.2, 8.2,
3.4 Hz, 1H, H14a), 3.04 5ddd, Jˆ11.2, 9.0, 4.2 Hz, 1H,
H11a), 2.90 5ddd, Jˆ9.0, 7.6, 6.3 Hz, 1H, H7a), 2.08 5brdddd,
Jˆ11.7, 7.2, 5.8, 4.5 Hz, 1H, H13), 2.05±1.94 5m, 2H,
2£H11), 1.94±1.90 5m, 2H, H13, H14), 1.83±1.73 5m, 4H,
2£H7, H6, H14), 1.65±1.58 5m, 2H, 2£H10), 1.40 5brddd,
Jˆ11.1, 9.5, 2.8 Hz, 1H, H11); 13C NMR5125 MHz,
CDCl3) d 128.0 5d, C3), 127.2 5d, C4), 84.0 5d, C5a), 83.8
5d, C11a), 83.2 5d, C7a), 82.7 5d, C12a), 79.0 5d, C4a), 77.3 5d,
C14a), 67.8 5t, C9), 65.8 5t, C2), 31.5 5t, C11), 30.1 5t, C6), 30.1
5t, C13), 28.9 5t, C14), 28.4 5t, C7), 25.9 5t, C10); HRMS Calcd
for C16H24O4 5M1): 280.16746; Found: 280.16763.
5.3.10. 12R,3S,200R,300S)-Acetic acid-2-[300-1benzyloxy-200-
methoxytetrahydropyran-200-yl)ethynyl]-tetrahydro-
pyran-3-yl ester 137). To a stirred solution of methyl acetal
35 5250 mg, 0.72 mmol) in dry CH2Cl2 57 mL) was added
Et3N 50.4 mL, 2.89 mmol), Ac2O 50.20 mL, 2.16 mmol),
and a catalytic amount of DMAP 55 mg). After the mixture
was stirred for 6 h at 258C, the reaction was quenched with a
saturated solution of NH4Cl 530 mL) and extracted with
CH2Cl2 53£20 mL). The combined CH2Cl2 phases were
washed with water 52£30 mL) and brine 52£20 mL) prior
to drying 5MgSO4) and solvent evaporation. Chroma-
tography of the crude residue on silica gel 5eluant: 30%
EtOAc in n-hexane) gave 37 5270 mg, 0.68 mmol, 97%).
37: colorless oil; Rfˆ0.52 5hexane/EtOAc, 7:3); [a]D
25
ˆ
5.3.7. 14aR,5aS,7aR,11aS,12aR,14aS)-2,2-Dimethyl-4,4a,
5a,6,7,7a,9,11a,12a,13,14,14a-dodecahydro-1,3,5,8,12-
pentaoxa-dibenzo[b,h]heptalene 114). Following the
described earlier protocol for RCM, 7 55.58 mg, 0.018
mmol) was converted to 1420 55.46 mg, 0.018 mmol, 98%).
115.28 5c 1.05, CHCl3); IR5neat) 3019, 2957, 1734,
1
1376, 1209 cm21; H NMR5400 MHz, CDCl ) d 7.38±
3
7.24 5m, 5H), 4.83 5br dd, Jˆ9.0, 4.5 Hz, 1H), 4.72 5d,
Jˆ12.3 Hz, 2H), 4.48 5d, Jˆ4.5 Hz, 1H), 3.95 5ddd, Jˆ
11.7, 8.9, 2.9 Hz, 1H), 3.62±3.59 5m, 1H), 3.58±3.54 5m,
3H), 3.46 5s, 3H), 2.13±2.10 5m, 1H), 2.07 5s, 3H), 1.87±
1.81 5m, 3H), 1.71±1.51 5m, 3H), 1.52±1.49 5m, 1H); 13C
5.3.8.
12R,3S,200R,300S)-2-[300-1Benzyloxy-200-methoxy-
tetrahydropyran-200-yl)ethynyl]-tetrahydropyran-3-ol 135).
To a stirred solution of hemiacetals 34 5800 mg, 1.79 mmol)
in dry MeOH 518 mL) was added CSA 5125 mg, 0.54 mmol)
at 08C. After being stirred for 24 h at 258C, the reaction
mixture was diluted with ether 550 mL) and water 52£
20 mL), and then dried 5MgSO4). Concentration followed
by ¯ash chromatography 5silica, 50% EtOAc in n-hexane)
gave 35 and 36 5609 mg, 1.76 mmol, 98%) as a 1:1 mixture
of a/b anomers, which were separated by successive
chromatographic puri®cations 5silica, 20±30% EtOAc in
n-hexane). 35: colorless oil; Rfˆ0.24 5hexane/EtOAc,
NMR5100 MHz, CDCl ) d 170.1 5s), 138.3 5s), 128.2 5d),
3
128.1 5d), 128.0 5d), 127.9 5d), 127.6 5d), 95.8 5s), 84.4 5s),
80.8 5s), 79.0 5d), 72.4 5t), 70.1 5d), 68.1 5d), 64.3 5t), 60.6
5t), 50.8 5q), 25.5 5t), 24.6 5t), 24.3 5t), 21.8 5t), 21.1 5q).
Anal. Calcd for C22H28O6: C, 68.02; H, 7.27. Found: C,
68.05; H, 7.38.
5.3.11. 12R,3S,200S,300S)-Acetic acid-2-[300-1benzyloxy-200-
methoxytetrahydropyran-200-yl)ethynyl]-tetrahydro-
pyran-3-yl ester 138). Prepared from 36 5250 mg,
0.72 mmol) by the same procedure used to convert 35 to
37. Flash column chromatography 5silica, 30% EtOAc in
n-hexane) gave 38 5262 mg, 0.68 mmol, 94%). 38: colorless
25
1:1); [a]D ˆ223.98 5c 1.33, CHCl3); IR5neat) 3604,
3019, 1453, 1078 cm21; H NMR5400 MHz, CDCl ) d
1
3
25
7.39±7.26 5m, 5H), 4.73 5s, 2H), 4.09 5d, Jˆ6.7 Hz, 1H),
3.94 5ddd, Jˆ11.7, 5.2, 2.8 Hz, 1H), 3.62±3.58 5m, 1H),
3.58±3.47 5m, 4H), 3.47 5s, 3H), 3.46 5ddd, Jˆ11.7, 8.5,
3.2 Hz, 1H), 2.66 5brs, 1H, D2O-exchangeable), 2.12±2.08
5m, 1H), 1.86±1.74 5m, 3H), 1.66±1.51 5m, 3H); 13C NMR
5100 MHz, CDCl3) d 138.2 5s), 128.3 5d), 128.1 5d), 128.0
5d), 127.9 5d), 127.6 5d), 95.8 5s), 83.8 5s), 82.3 5s), 79.0 5d),
oil; Rfˆ0.66 5hexane/EtOAc, 7:3); [a]D ˆ15.708 5c 0.84,
1
CHCl3); IR5neat) 3019, 2957, 1734, 1245, 1092 cm 21; H
NMR5400 MHz, CDCl ) d 7.39±7.22 5m, 5H), 4.84±4.82
3
5m, 1H), 4.77 5d, Jˆ12.1 Hz, 1H), 4.63 5d, Jˆ12.1 Hz, 1H),
4.48 5d, Jˆ4.5 Hz, 1H), 3.95 5ddd, Jˆ11.6, 9.1, 2.9 Hz, 1H),
3.71±3.68 5m, 1H), 3.66 5ddd, Jˆ14.8, 11.6, 3.4 Hz, 1H),
3.57 5ddd, Jˆ11.6, 4.4, 4.4 Hz, 1H), 3.46 5s, 3H), 3.35 5dd,

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1935
Jˆ7.7, 3.8 Hz, 1H), 2.11±2.08 5m, 1H), 2.04 5s, 3H), 1.90±
1.81 5m, 4H), 1.67±1.63 5m, 1H), 1.45±1.42 5m, 2H); 13C
NMR5100 MHz, CDCl ) d 170.1 5s), 138.7 5s), 128.2 5d),
128.1 5d), 127.8 5d), 127.7 5d), 127.4 5d), 98.9 5s), 83.1 5s),
82.5 5s), 77.5 5d), 72.6 5t), 70.2 5d), 68.2 5d), 64.3 5t), 62.7
5t), 51.0 5q), 25.9 5t), 25.6 5t), 22.2 5t), 21.8 5t), 21.1 5q).
Anal. Calcd for C22H28O6: C, 68.02; H, 7.27. Found: C,
68.01; H, 7.38.
ture for 1 h. Et3N 50.56 mL, 4.0 mmol) was then added at
2788C. The mixture was allowed to warm to 258C over a
1 h period, diluted with CH2Cl2 510 mL), and washed with
brine 52£10 mL). The organic solution was dried 5MgSO4)
and concentrated to afford a crude product that was puri®ed
by ¯ash column chromatography 5silica, 20% EtOAc in
n-hexane) to yield the ketone 41 579 mg, 0.27 mmol,
76%). 41: colorless oil; Rfˆ0.45 5hexane/EtOAc, 7:3);
3
25
[a]D ˆ257.28 5c 0.77, CHCl3); IR5neat) 3031, 1733,
5.3.12. 12R,3S,200R,300S)-Acetic acid-2-[-20-1-300-hydroxy-
200-methoxytetrahydropyran-200-yl)vinyl]-tetrahydro-
pyran-3-yl ester 139). 10% Pd±BaSO4 catalyst 550 mg) was
added to a stirred solution of 37 5250 mg, 0.64 mmol) in
EtOAc 510 mL) and quinoline 50.1 equiv.) under H2 atmos-
phere. After the mixture was stirred for 6 h at 258C, the
catalyst was ®ltered off and the solvent was removed
under vacuum to give, after ¯ash column puri®cation
550% EtOAc in n-hexane) compound 39 5123 mg, 0.41
mmol, 64%). 39: colorless oil; Rfˆ0.66 5hexane/EtOAc,
1602, 1247, 1091, 1027 cm21 1H NMR5400 MHz,
;
CDCl3) d 5.71 5dd, Jˆ12.2, 9.0 Hz, 1H), 5.60 5d, Jˆ
12.2 Hz, 1H), 4.55 5ddd, Jˆ11.8, 8.9, 4.3 Hz, 1H), 4.46
5dd, Jˆ8.9, 8.9 Hz, 1H), 4.01 5ddd, Jˆ11.5, 11.5, 2.9 Hz,
1H), 3.97 5ddd, Jˆ11.3, 1.9, 1.9 Hz, 1H), 3.84 5ddd, Jˆ11.5,
2.5, 2.5 Hz, 1H), 3.38 5ddd, Jˆ11.3, 11.3, 3.7 Hz, 1H), 3.29
5s, 3H), 2.84 5ddd, Jˆ14.8, 12.2, 6.6 Hz, 1H), 2.44 5ddd,
Jˆ14.8, 3.4, 3.4 Hz, 1H), 2.18±2.16 5m, 1H), 2.10±2.06 5m,
2H), 1.95 5s, 3H), 1.74±1.68 5m, 2H), 1.47 5dddd, Jˆ17.3,
12.1, 11.8, 5.1 Hz, 1H); 13C NMR5100 MHz, CDCl ) d
3
25
7:3); [a]D ˆ269.48 5c 1.01, CHCl3); IR5neat) 3400,
202.3 5s), 170.2 5s), 134.4 5d), 128.9 5s), 100.9 5s), 75.2
5d), 71.6 5d), 66.8 5t), 59.7 5t), 49.4 5q), 35.6 5t), 28.9 5t),
27.4 5t), 24.9 5t), 21.2 5q). Anal. Calcd for C15H22O6: C,
60.39; H, 7.93. Found: C, 60.51; H, 7.71.
2949, 1732, 1246, 1071 cm21
;
1H NMR5400 MHz,
CDCl3) d 5.61 5dd, Jˆ12.1, 9.0 Hz, 1H), 5.55 5d, Jˆ
12.1 Hz, 1H), 4.65 5ddd, Jˆ10.5, 9.0, 4.8 Hz, 1H), 4.43
5dd, Jˆ9.0, 9.0 Hz, 1H), 3.87 5ddd, Jˆ10.8, 2.5, 1.9 Hz,
1H), 3.55 5ddd, Jˆ11.1, 3.0, 1.6 Hz, 1H), 3.47±3.35 5m,
3H), 3.34 5brs, 1H, D2O-exchangeable), 3.24 5s, 3H), 2.13
5br ddd, Jˆ12.1, 4.5, 3.4 Hz, 1H), 1.97 5s, 3H), 1.83±1.55
5m, 6H), 1.50 5dddd, Jˆ12.1, 11.2, 10.5, 5.0 Hz, 1H); 13C
5.3.15. 12R,3S,200S)-Acetic acid-2-[-20-1-200-methoxy-300-
oxo-tetrahydropyran-200-yl)vinyl]-tetrahydropyran-3-yl
ester 142). Prepared from 40 5129 mg, 0.43 mmol) follow-
ing the same procedure used to convert 39 to 41. Flash
column chromatography 5silica, 20% EtOAc in n-hexane)
gave 42 5101 mg, 0.34 mmol, 79%). 42: colorless oil; Rfˆ
NMR5100 MHz, CDCl ) d 169.9 5s), 135.1 5d), 131.7 5d),
3
100.4 5s), 73.9 5d), 72.1 5d), 71.2 5d), 67.2 5t), 59.8 5t), 48.8
5q), 28.8 5t), 26.6 5t), 25.1 5t), 24.8 5t), 21.0 5q). Anal. Calcd
for C15H24O6: C, 59.98; H, 8.05. Found: C, 60.10; H, 8.24.
25
0.57 5hexane/EtOAc, 7:3); [a]D ˆ21.38 5c 0.71, CHCl3);
1
IR5neat) 3026, 3018, 1733, 1446, 1218, 1080 cm 21; H
NMR5400 MHz, CDCl ) d 5.76 5dd, Jˆ12.0, 9.0 Hz, 1H),
3
5.3.13. 12R,3S,200S,300S)-Acetic acid-2-[-20-1-300-hydroxy-
200-methoxytetrahydropyran-200-yl)vinyl]-tetrahydro-
pyran-3-yl ester 140). Prepared from 38 5250 mg,
0.64 mmol) following the same procedure used to convert
37 to 39. Flash column chromatography 5silica, 30% EtOAc
in n-hexane) gave 40 5115 mg, 0.38 mmol, 59%). 40: color-
5.46 5d, Jˆ12.0 Hz, 1H), 4.66 5ddd, Jˆ10.2, 9.0, 4.5 Hz,
1H), 4.27 5dd, Jˆ9.0, 9.0 Hz, 1H), 3.99 5ddd, Jˆ11.7,
11.7, 3.0 Hz, 1H), 3.87 5brd, Jˆ11.2 Hz, 1H), 3.76 5ddd,
Jˆ11.7, 3.1, 2.0 Hz, 1H), 3.37 5ddd, Jˆ11.2, 11.2, 4.2 Hz,
1H), 3.30 5s, 3H), 2.84 5ddd, Jˆ14.3, 12.3, 6.6 Hz, 1H), 2.43
5dddd, Jˆ14.3, 4.9, 3.2, 1.6 Hz, 1H), 2.19 5ddddd, Jˆ13.4,
12.3, 11.7, 4.9, 3.1 Hz, 1H), 2.07 5s, 3H), 2.06±2.03 5m,
2H), 1.96±1.71 5m, 2H), 1.54 5ddddd, Jˆ11.2, 10.2, 10.2,
5.5, 1.6 Hz, 1H); 13C NMR5100 MHz, CDCl 3) d 201.7 5s),
170.5 5s), 134.4 5d), 128.9 5s), 101.3 5s), 74.9 5d), 71.4 5d),
66.7 5t), 59.6 5t), 49.5 5q), 35.6 5t), 28.7 5t), 27.9 5t), 24.8 5t),
21.2 5q). Anal. Calcd for C15H22O6: C, 60.39; H, 7.93.
Found: C, 60.58; H, 7.71.
25
less oil; Rfˆ0.21 5hexane/EtOAc, 7:3); [a]D ˆ18.38 5c
1.42, CHCl3); IR5neat) 3400, 3013, 1734, 1247,
1
1088 cm21; H NMR5400 MHz, CDCl ) d 5.63 5dd, Jˆ
3
11.9, 9.0 Hz, 1H), 5.43 5d, Jˆ11.9 Hz, 1H), 4.56 5ddd,
Jˆ10.0, 10.0, 4.5 Hz, 1H), 4.43 5dd, Jˆ10.0, 9.0 Hz, 1H),
3.91 5ddd, Jˆ11.2, 2.2, 2.2 Hz, 1H), 3.65±3.63 5m, 2H),
3.57 5brs, 1H), 3.41 5ddd, Jˆ11.2, 11.2, 3.0 Hz, 1H), 3.20
5s, 3H), 2.73 5brs, 1H, D2O-exchangeable), 2.15 5br ddd,
Jˆ12.0, 4.5, 3.6 Hz, 1H), 1.99 5s, 3H), 1.98±1.96 5m,
2H), 1.75±1.68 5m, 3H), 1.48 5dddd, Jˆ12.0, 11.0, 10.0,
4.6 Hz, 1H), 1.29±1.26 5m, 1H); 13C NMR5100 MHz,
CDCl3) d 170.1 5s), 134.3 5d), 132.8 5d), 100.7 5s), 74.5
5d), 71.7 5d), 68.5 5d), 67.2 5t), 60.6 5t), 49.2 5q), 29.1 5t),
25.5 5t), 25.0 5t), 21.0 5q), 18.4 5t). Anal. Calcd for
C15H24O6: C, 59.98; H, 8.05. Found: C, 59.86; H, 8.05.
5.3.16.
12R,3S,200R)-2-[-20-1-200-Methoxy-300-oxo-tetra-
hydropyran-200-yl)vinyl]-tetrahydropyran-3-ol 143). A
mixture of acetate 41 550 mg, 0.17 mmol), MeONa catalytic
54 mg, 0.07 mmol), and MeOH 510 mL) was stirred at 258C
for 30 min. Evaporation of the solvent followed by ¯ash
chromatography 5silica, 30% EtOAc in n-hexane) gave
hydroxy-ketone 43 535 mg, 0.14 mmol, 80%). 43: colorless
25
oil; Rfˆ0.32 5hexane/EtOAc, 1:1); [a]D ˆ232.48 5c 0.82,
5.3.14. 12R,3S,200R)-Acetic acid-2-[-20-1-200-methoxy-300-
oxo-tetrahydropyran-200-yl)vinyl]-tetrahydropyran-3-yl
ester 141). Oxalyl chloride 50.10 mL, 1.2 mmol) was slowly
added to a cold 52788C) and stirred solution of DMSO
50.14 mL, 2.0 mmol) in dry CH2Cl2 55 mL) under argon.
After the solution was stirred for 10 min, the alcohol 39
5104 mg, 0.35 mmol) in CH2Cl2, 55 mL) was dropwise
added at 2788C, and stirring was continued at that tempera-
CHCl3); IR5neat) 3605, 3018, 2942, 1720, 1604, 1162,
1
988 cm21; H NMR5400 MHz, CDCl ) d 5.83 5dd, Jˆ
3
12.0, 9.0 Hz, 1H), 5.62 5d, Jˆ12.0 Hz, 1H), 4.06 5ddd,
Jˆ11.4, 11.4, 3.0 Hz, 1H), 3.92 5brdd, Jˆ11.3, 4.2 Hz,
1H), 3.83 5ddd, Jˆ11.4, 2.5, 2.5 Hz, 1H), 3.57 5dd, Jˆ9.8,
9.0 Hz, 1H), 3.45 5brs, 1H, D2O-exchangeable), 3.36 5ddd,
Jˆ11.3, 11.3, 3.2 Hz, 1H), 3.29 5s, 3H), 3.02 5ddd, Jˆ10.0,
9.8, 4.3 Hz, 1H), 2.86 5ddd, Jˆ14.5, 12.3, 7.0 Hz, 1H), 2.43

1936
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
5ddd, Jˆ14.5, 3.5, 3.5 Hz, 1H), 2.19±2.15 5m, 2H), 2.08±
2.04 5m, 1H), 1.66±1.63 5m, 2H), 1.36 5dddd, Jˆ12.5, 12.5,
11.0, 5.2 Hz, 1H); 13C NMR5100 MHz, CDCl 3) d 201.3 5s),
134.4 5d), 128.9 5d), 100.8 5s), 81.4 5d), 78.2 5d), 67.4 5t),
59.7 5t), 49.3 5q), 35.6 5t), 29.8 5t), 27.4 5t), 25.3 5t). Anal.
Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C, 60.82; H,
7.90.
NMR5100 MHz, CDCl ) d 141.2 5d), 128.8 5d), 100.9 5s),
3
99.8 5s), 79.3 5d), 68.2 5d), 67.3 5t), 60.1 5t), 50.1 5q), 49.2
5q), 33.2 5t), 31.0 5t), 25.0 5t), 23.2 5t). Anal. Calcd for
C14H22O5: C, 62.20; H, 8.20. Found: C, 62.12; H, 8.37.
5.3.19. 14aS,5aR,9aR,11aR)-2,3,4a,5a,6,7,8,9a,11a-Deca-
hydro-1,5,9-trioxa-dibenzo [a,d]cycloheptene 146). To a
solution of 43 540 mg, 0.15 mmol) in freshly distilled
CH3CN 53.5 mL) at 2308C were added Et3SiH 50.36 mL,
2.28 mmol) and then BF3´OEt2 50.3 mL, 2.28 mmol). The
resulting solution was stirred for 3 h at 08C. The reaction
mixture was then diluted with ether 520 mL) and washed
with saturated NaHCO3 52£10 mL), and brine 52£10 mL).
The organic layer was dried 5MgSO4) and concentrated
under vacuum. Flash column chromatography 5silica,
5±10% EtOAc in n-hexane) procedure 46 524 mg,
0.11 mmol, 73%) and its less polar epimer 47 52.6 mg,
0.012 mmol, 8%). 46: colorless oil; Rfˆ0.45 5hexane/
5.3.17. 14aR,5aS,9aR,11aS)-11a-Methoxy-3,4,5a,6,7,8,9a,
11a-octahydro-2H-1,5,9-trioxa-dibenzo[a,d]cyclohepten-
4a-ol 144). Prepared from 42 550 mg, 0.17 mmol) following
the same procedure used to convert 41 to 43. Flash column
chromatography 5silica, 30% EtOAc in n-hexane) gave
hemiacetal 44 542 mg, 0.16 mmol, 94%). 44: colorless
prism; mp 1428C 5hexane/ether); Rfˆ0.29 5hexane/EtOAc,
25
7:3); [a]D ˆ224.38 5c 0.74, CHCl3); IR5KBr) 3400, 3010,
1
1719, 1463, 1306, 1211, 1027 cm21; H NMR5400 MHz,
CDCl3) d 5.92 5dd, Jˆ12.2, 2.5 Hz, 1H, H11), 5.38 5dd,
Jˆ12.2, 2.5 Hz, 1H, H10), 4.07 5ddd, Jˆ9.5, 2.5, 2.5 Hz,
1H, H9a), 3.87±3.80 5m, 2H, H5a, He8), 3.64±3.56 5m, 2H,
2£H2), 3.33±3.25 5m, 1H, Ha8), 3.22 5s, 3H, OCH3), 2.03 5s,
1H, OH), 2.00±1.91 5m, 3H, H3, H6, H4), 1.68±1.58 5m, 4H,
H4, H6, 2£H7), 1.50±1.48 5m, 1H, H3); 13C NMR5100 MHz,
CDCl3) d 139.9 5d, C11), 127.9 5d, C10), 100.6 5s, C11a), 94.4
5s, C4a), 79.3 5d, C9a), 68.0 5d, C5a), 67.1 5t, C8), 59.8 5t, C2),
49.0 5q, OCH3), 32.1 5t, C4), 30.7 5t, C6), 25.3 5t, C7), 22.9 5t,
C3); 1H NMR5400 MHz, C 6D6) d 6.02 5dd, Jˆ12.2, 2.5 Hz,
1H, H11), 5.40 5dd, Jˆ12.2, 2.5 Hz, 1H, H10), 4.24 5ddd,
Jˆ9.5, 2.5, 2.5 Hz, 1H, H9a), 3.98 5ddd, Jˆ13.0, 9.5,
4.6 Hz, 1H, H5a), 3.68 5brd, Jˆ12.0 Hz, 1H, He8), 3.47
5ddd, Jˆ11.0, 11.0, 2.5 Hz, 1H, Ha2), 3.39±3.18 5m, 1H,
He2), 3.13 5s, 3H, OCH3), 3.01 5ddd, Jˆ13.0, 12.0,
2.0 Hz, 1H, Ha8), 2.75 5s, 1H, OH), 2.28 5ddd, Jˆ13.3,
13.3, 4.5 Hz, 1H, Ha4), 2.00±1.94 5m, 2H, He3, He6), 1.83
5brd, Jˆ13.3 Hz, 1H, He4), 1.59 5dddd, Jˆ13.4, 13.4, 13.0,
4.1 Hz, 1H, Ha6), 1.44 5ddddd, Jˆ13.4, 13.0, 13.0, 4.0,
4.0 Hz, 1H, Ha7), 1.17±1.13 5m, 2H, He7, Ha3); 13C NMR
5100 MHz, C6D6) d 140.0 5d, C11), 128.1 5d, C10), 100.8 5s,
C11a), 94.4 5s, C4a), 79.6 5d, C9a), 68.1 5d, C5a), 66.1 5t, C8),
59.5 5t, C2), 48.4 5q, OCH3), 32.3 5t, C4), 31.1 5t, C6), 25.4 5t,
C7), 23.0 5t, C3). Anal. Calcd for C13H20O5: C, 60.92; H,
7.87. Found: C, 60.66; H, 7.97.
25
EtOAc, 7:3); [a]D ˆ226.08 5c 0.58, CHCl3); IR5neat)
3011, 2950, 1263, 1220, 1040, 1029 cm21 1H NMR
;
5400 MHz, CDCl3) d 5.92 5brd, Jˆ10.4 Hz, 1H, H10), 5.66
5ddd, Jˆ10.4, 2.1, 2.1 Hz, 1H, H11), 4.28 5ddd, Jˆ4.0, 2.1,
2.1 Hz, 1H, H9a), 3.94 5brdd, Jˆ11.5, 4.5 Hz, 1H, He2),
3.89±3.82 5m, 2H, H5a, He8), 3.79 5ddd, Jˆ14.4, 13.6,
7.0 Hz, 1H, Ha8), 3.60 5brd, Jˆ8.3 Hz, 1H, H11a), 3.47
5ddd, Jˆ11.5, 11.5, 4.0 Hz, 1H, Ha2), 3.24 5ddd, Jˆ11.5,
8.3, 4.0 Hz, 1H, H4a), 2.10 5dddd, Jˆ12.0, 4.0, 4.0, 4.0 Hz,
1H, He4), 1.90±1.83 5m, 3H, 2£H7, H6), 1.78±1.70 5m, 3H,
2£H3, H6), 1.61±1.55 5m, 1H, Ha4); 13C NMR5100 MHz,
CDCl3) d 129.7 5d, C10), 127.5 5d, C11), 80.4 5d, C5a), 78.1
5d, C9a), 75.6 5d, C11a), 75.0 5d, C4a), 68.6 5t, C8), 68.2 5t, C2),
29.4 5t, C4), 27.3 5t, C7), 25.8 5t, C3), 25.7 5t, C6). Anal. Calcd
for C12H18O3: C, 68.53; H, 8.70. Found: C, 68.43; H, 9.00.
Compound 46 512 mg, 0.05 mmol) was hydrogenated 510%
Pd±C cat/H2/EtOAc/258C/30 min) to give the known full-
hydrogenated derivative.28b
5.3.20. meso-14aS,5aR,9aS,11aR)-2,3,4a,5a,6,7,8,9a,11a-
Decahydro-1,5,9-trioxa-dibenzo [a,d]cycloheptene 147).
To a solution of 45 562 mg, 0.23 mmol) in CH3CN
510 mL) at 2788C were added Et3SiH 50.6 mL, 3.45
mmol) and then BF3´OEt2 50.43 mL, 3.45 mmol). The
resulting solution was stirred for 2 h at 2158C. The reaction
mixture was then diluted with ether 530 mL) and washed
with saturated NaHCO3 52£10 mL) and brine 52£15 mL).
The organic layer was dried 5MgSO4) and concentrated
under vacuum. Flash column chromatography 5silica, 10%
EtOAc in n-hexane) afforded 47 538 mg, 0.18 mmol, 78%).
47: colorless oil; Rfˆ0.50 5hexane/EtOAc, 4:1); IR5neat)
3011, 2950, 2856, 1263, 1093, 1029 cm21 1H NMR
;
5400 MHz, CDCl3) d 5.57 5s, 1H, H10), 3.89 5brd, Jˆ
10.5 Hz, 1H, He2), 3.73 5d, Jˆ8.2 Hz, 1H, H9a), 3.31 5ddd,
Jˆ11.0, 10.5, 4.0 Hz, 1H, Ha2), 3.24 5ddd, Jˆ11.5, 8.2,
4.5 Hz, 1H, H4a), 2.05 5brd, Jˆ9.0 Hz, 1H, He4), 1.70±
1.64 5m, 2H, 2£H3), 1.51±1.43 5m, 1H, Ha4); 13C NMR
5100 MHz, CDCl3) d 132.1 5d, C10), 81.2 5d, C9a), 79.2 5d,
C4a), 67.4 5t, C2), 31.2 5t, C4), 25.4 5t, C3). Anal. Calcd for
C12H18O3: C, 68.53; H, 8.70. Found: C, 68.43; H, 9.10.
5.3.18. 14aR,5aS,9aR,11aS)-4a,11a-Dimethoxy-3,4,5a,6,
7,8,9a,11a-octahydro-2H-1,5,9-trioxa-dibenzo[a,d]cyclo-
heptene 145). To a stirred solution of hemiacetal 44 585 mg,
0.33 mmol) in dry DMF 510 mL) at 2308C were added NaH
50.83 mmol, 2.5 equiv., 60% dispersion in mineral oil) and
MeI 50.11 mL, 234 mg, 1.65 mmol, 5.0 equiv.). The result-
ing solution was stirred for 8 h at 08C. The reaction mixture
was then diluted with ether 530 mL) and washed with 5%
aqueous HCl solution 52£25 mL) and brine 52£25 mL). The
organic layer was dried 5MgSO4) and concentrated under
vacuum. Flash column chromatography 5silica, 5% EtOAc
in n-hexane) afforded 45 554.4 mg, 0.20 mmol, 61%). 45:
colorless prism; mp 928C 5hexane); Rfˆ0.61 5hexane/
25
EtOAc, 3:1); [a]D ˆ212.38 5c 0.93, CHCl3); IR5KBr)
1
3012, 1604, 1353, 1110, 982 cm21; H NMR5400 MHz,
CDCl3) d 5.96 5dd, Jˆ12.0, 1.5 Hz, 1H), 5.42 5dd, Jˆ
12.0, 1.5 Hz, 1H), 4.04 5ddd, Jˆ9.5, 1.5, 1.5 Hz, 1H),
3.86±3.79 5m, 2H), 3.62±3.55 5m, 2H), 3.30 5ddd, Jˆ
11.0, 3.0, 3.0 Hz, 1H), 3.23 5s, 3H), 3.18 5s, 3H), 1.98±
1.89 5m, 3H), 1.68±1.56 5m, 4H), 1.50±1.42 5m, 1H); 13C
5.3.21. 12S,4aR,8aS)-Spiro[2,4a,6,7,8a-hexahydropyran-
[3,2-b]-pyran-2,2-tetrahydropyran-30-one] 148). To a
solution of 43 532 mg, 0.13 mmol) in freshly distilled
CH3CN 51.3 mL) at 2308C was added BF3´OEt2

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1937
50.03 mL, 0.26 mmol). The resulting solution was stirred for
30 min at 2308C. The reaction mixture was then diluted
with ether 510 mL) and washed with saturated NaHCO3
52£5 mL) and brine 52£5 mL). The organic layer was
dried 5MgSO4) and concentrated under vacuum. Flash
column chromatography 5silica, 20% EtOAc in n-hexane)
gave a mixture of spiroketones 48 and 49 528 mg,
0.12 mmol, 93%). Compounds 48 524.3 mg, 0.11 mmol,
85%) and 49 52.7 mg, 0.01 mmol, 8%) were isolated by
successive chromatographic puri®cations 5silica, 5±10%
EtOAc in n-hexane). 48: colorless oil; Rfˆ0.52 5hexane/
diluted with ether 5100 mL). The ethereal portion was dried
5MgSO4) and concentrated and the residue subjected to ¯ash
chromatography 5silica, 30% EtOAc in n-hexane) to give 52
52.33 g, 4.65 mmol, 93%) as a 1:1 mixture of isomers. 52:
colorless oil; Rfˆ0.45 5hexane/EtOAc, 7:3); IR5neat) 3692,
3012, 2953, 1253, 1129, 987 cm21. Anal. Calcd for
C28H42O6Si: C, 66.92; H, 8.36. Found: C, 67.12; H, 8.40.
5.3.24.
tetrahydropyran-200-yl)
12R/2S,3S,4aR,8aS,200S,300R)-2-1300-Hydroxy-
ethynyl-2-methoxy-3-benzyl-
oxy-octatetrahydropyran[3,2-b] pyrane 153). The com-
pound 53 was prepared from the hemiacetal 52 52.33 g,
4.65 mmol) following the same procedure used to convert
hemiacetal 34 to methyl acetal 35. Flash column chroma-
tography 5silica, 30% EtOAc in n-hexane) gave 53 51.8 g,
4.46 mmol, 96%). 53: yellowish oil; Rfˆ0.34 5hexane/
EtOAc, 1:1); IR5neat) 3595, 3020, 2858, 1266, 1170,
989 cm21. Anal. Calcd for C23H30O6: C, 68.66; H, 7.46.
Found: C, 68.46; H, 7.55.
25
EtOAc, 7:3); [a]D ˆ263.98 5c 1.02, CHCl3); IR5neat)
3019, 1732, 1306, 1271, 1068, 962 cm21
;
1H NMR
5400 MHz, CDCl3) d 6.08 5d, Jˆ10.4 Hz, 1H, H3), 5.69
5dd, Jˆ10.4, 2.4 Hz, 1H, H4), 4.20 5ddd, Jˆ12.0, 11.5,
0
2.8 Hz, 1H, Ha6 ), 3.94 5brd, Jˆ11.3 Hz, 1H, He6), 3.73
0
5brdd, Jˆ11.5, 4.7 Hz, 1H, He6 ), 3.66 5ddd, Jˆ11.5, 8.9,
4.1 Hz, 1H, H8a), 3.59 5ddd, Jˆ8.9, 2.4, 2.0 Hz, 1H, H4a),
3.43 5ddd, Jˆ11.3, 11.3, 3.8 Hz, 1H, Ha6), 2.88 5ddd,
0
Jˆ14.0, 13.4, 6.7 Hz, 1H, Ha4 ), 2.42 5ddd, Jˆ14.2, 4.4,
2.1, 2.1 Hz, 1H, He4 ), 2.17 5ddddd, Jˆ13.4, 13.4, 12.0,
5.3.25. 12R/2S,3S,4aR,8aS,200S,300R)-2-1300-Acetoxy-tetra-
hydropyran-200-yl) ethynyl-2-methoxy-3-benzyloxy-octa-
hydropyran[3,2-b] pyrane 154). Prepared from 53 51.77 g,
4.40 mmol) by the same procedure used to convert 35 to 37.
Flash column chromatography 5silica, 30% EtOAc in
n-hexane) gave 54 51.91 g, 4.31 mmol, 98%). 54: yellowish
oil; Rfˆ0.42 5hexane/EtOAc, 2:1); IR5neat) 3020, 2957,
1734, 1376, 1340, 1210 cm21. Anal. Calcd for C25H32O7:
C, 67.56; H, 7.21. Found: C, 67.66; H, 7.43.
0
0
0
4.7, 4.4 Hz, 1H, Ha5 ), 2.10±2.06 5m, 2H, He5 , He8),
1.79±1.76 5m, 2H, 2£H7), 1.57 5dddd, Jˆ12.0, 12.0, 11.5,
5.5 Hz, 1H, Ha8); 13C NMR5100 MHz, CDCl 3) d 202.6 5d,
0
C3 ), 132.9 5d, C3), 125.4 5s, C4), 96.9 5s, C2), 75.2 5d, C4a),
0
70.4 5d, C8a), 68.3 5t, C6), 60.2 5t, C6 ), 35.7 5t, C4 ), 28.8 5t,
0
0
C8), 28.4 5t, C5 ), 25.7 5t, C7). Anal. Calcd for C12H16O4: C,
64.27; H, 7.19. Found: C, 64.15; H, 7.14. Hemiacetal 44
542 mg, 0.16 mmol), following the earlier described con-
ditions gave compounds 48 532 mg, 0.14 mmol, 87%) and
49 53.6 mg, 0.02 mmol, 12%).
5.3.26. 12R/2S,3S,4aR,8aS,200S,300R)-2-[20-1300-Acetoxy-
tetrahydropyran-200-yl)
vinyl]-2-methoxy-octahydro-
5.3.22.
12R,4aR,8aS)-Spiro[2,4a,6,7,8,8a-hexahydro-
pyran[3,2-b]pyran-3-ol 155). Prepared from 54 51.89 g,
4.26 mmol) by the same procedure followed to convert 37
to 39. Flash column chromatography 5silica, 30% EtOAc in
n-hexane) gave 55 5895 mg, 2.52 mmol, 59%). 55: colorless
oil; Rfˆ0.53 5hexane/EtOAc, 2:1); IR5neat) 3010, 1734,
1625, 1370, 1220 cm21. Anal. Calcd for C18H28O7: C,
60.67; H, 7.87. Found: C, 60.60; H, 7.92.
pyran[3,2-b]-pyran-2,20-tetrahydropyran-30-one] 149).
25
Colorless oil; Rfˆ0.61 5hexane/EtOAc, 7:3); [a]D
ˆ
111.48 5c 0.22, CHCl3); IR5neat) 3019, 2953, 1732,
1306, 1271, 1210 cm21; H NMR5400 MHz, CDCl ) d
1
3
6.15 5d, Jˆ10.3 Hz, 1H, H3), 5.69 5dd, Jˆ10.3, 2.5 Hz,
0
1H, H4), 4.36 5ddd, Jˆ11.8, 11.8, 2.6 Hz, 1H, Ha6 ), 3.93
5brd, Jˆ11.5 Hz, 1H, He6), 3.78 5dddd, Jˆ11.8, 5.0, 2.5,
2.0 Hz, 1H, He6 ), 3.73 5ddd, Jˆ8.6, 2.5, 1.5 Hz, 1H, H4a),
5.3.27. 12R/2S,3S,4aR,8aS,200S,300R)-2-[20-1300-Acetoxy-
0
3.48±3.42 5m, 1H, Ha6), 3.32 5ddd, Jˆ10.7, 8.6, 4.5 Hz, 1H,
tetrahydropyran-200-yl)
vinyl]-2-methoxy-octahydro-
0
H8a), 2.94 5ddd, Jˆ15.0, 13.1, 6.5 Hz, 1H, Ha4 ), 2.45 5ddd,
pyran[3,2-b]pyran-3-one 156). Prepared from 55
5890 mg, 2.50 mmol) by the same procedure to convert 39
to 41. Flash column chromatography 5silica, 30% EtOAc in
n-hexane) afforded 56 5726 mg, 2.05 mmol, 82%). 56:
colorless oil; Rfˆ0.62 5hexane/EtOAc, 3:1); IR5neat)
3020, 1736, 1720, 1602, 1247, 1028 cm21. Anal. Calcd
for C18H26O7: C, 61.02; H, 7.34. Found: C, 61.33; H, 7.26.
0
Jˆ15.0, 2.5, 2.5 Hz, 1H, He4 ), 2.16 5ddddd, Jˆ18.1, 13.1,
0
0
11.8, 5.0, 5.0 Hz, 1H, Ha5 ), 2.10±2.06 5m, 1H, H5 ), 1.98
5brd, Jˆ11.5 Hz, 1H, He8), 1.76±1.71 5m, 2H, 2£H7), 1.73±
1.68 5m, 1H, Ha8); 13C NMR5100 MHz, CDCl 3) d 202.4 5d,
0
C3 ), 133.0 5d, C3), 125.2 5s, C4), 97.0 5s, C2), 75.3 5d, C4a),
0
70.4 5d, C8a), 68.8 5t, C6), 60.2 5t, C6 ), 35.6 5t, C4 ), 28.8 5t,
0
0
C8), 28.6 5t, C5 ), 25.7 5t, C7). Anal. Calcd for C12H16O4: C,
64.27; H, 7.19. Found: C, 64.10; H, 7.14.
5.3.28. 12S,4aR,8aS,200S,300R)-2-[20-1300-Hydroxy-tetra-
hydropyran-200-yl)vinyl]-2-methoxy-octahydropyran-
[3,2-b]pyran-3-one 157). Prepared from 56 5708 mg,
2.0 mmol) by the same procedure to convert 41 to 43.
Flash column chromatography 5silica, 30% EtOAc in
n-hexane) gave 57 and 58 5537 mg, 1.72 mmol, 86%)
which were separated by successive chromatographic
puri®cations 5silica, 5±10% EtOAc in n-hexane). 57: color-
5.3.23. 12R/2S,3S,4aR,8aS,200S,300R)-2-1300-tert-Butyldi-
methylsilanyloxy-tetrahydropyran-200-yl)
ethynyl-3-
1benzyloxy)octahydropyran[3,2-b] pyran-2-ol 152). The
vinyl dibromide 50 52.0 g, 5.0 mmol) in a stirred solution
of dry THF 530 mL) at 2788C was treated dropwise with
n-BuLi 55.88 mL, 10.0 mmol, 1.7 M in THF). The reaction
mixture was then warmed to 2358C, and stirring continued
for 1 h. The solution was cooled to 2788C and the lactone
51 51.26 g, 4.8 mmol) in dry THF 55 mL) was added drop-
wise over a 10 min period. After 1.5 h at 258C, the reaction
was carefully quenched with saturated NH4Cl 520 mL) and
25
less oil; Rfˆ0.39 5hexane/EtOAc, 9:1); [a]D ˆ24.58 5c
1.18, CHCl3); IR5neat) 3469, 2946, 1730, 1216,
1
1040 cm21; H NMR5400 MHz, CDCl ) d 5.91 5dd, Jˆ
3
0
0
12.0, 8.8 Hz, 1H, H2 ), 5.71 5d, Jˆ12.0 Hz, 1H, H1 ),
00
3.96±3.88 5m, 2H, H4a, He6 ), 3.68 5dd, Jˆ9.0, 8.8 Hz,

1938
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
00
1H, H2 ), 3.44 5ddd, Jˆ10.0, 9.0, 4.5 Hz, 1H, H8a), 3.42±
Compound 59 547 mg, 0.15 mmol) was reduced to the
known compound27f 60 522.5 mg, 0.085 mmol, 57%) fol-
lowing the same procedure to convert 45 to 47.
00
3.36 5m, 3H, Ha6 , 2£H6), 3.33 5ddd, Jˆ12.0, 9.0, 3.5 Hz,
00
1H, H3 ), 3.30 5s, 3H, OCH3), 3.05 5brdd, Jˆ16.2, 6.4 Hz,
00
1H, H3 ), 2.39 5dd, Jˆ16.2, 10.9 Hz, 1H, Ha4), 2.20 5brdd,
Jˆ12.5, 4.5 Hz, 1H, He8), 2.18 5brdd, Jˆ13.0, 3.5 Hz, 1H,
5.3.31.
12S,4aS,8aR,40aR,80aS)-Spiro-12,4a,6,7,8,8a)-
He4 ), 1.98 5brs, 1H, OH), 1.82±1.73 5m, 2H, 2£H7), 1.72±
hexahydro[3,2-b]pyran-2-20-octahydropyran[3,2-b]pyran-
3-one 161). Treatment of hydroxy-ketone 57 5130 mg,
0.42 mmol) under the same conditions used to convert 43
to 48 and 49, gave a 1:1 mixture of spiroketones 61 and 62
5118 mg, 0.42 mmol, 100%). Flash column chromatography
5silica, 5±15% EtOAc in n-hexane) gave 61 554 mg,
0.19 mmol) and its more polar epimer 62 552 mg,
0.19 mmol). 61: colorless oil; Rfˆ0.78 5hexane/EtOAc,
00
00
1.65 5m, 2H, 2£H5 ), 1.58±1.54 5m, 1H, He8), 1.46 5dddd,
Jˆ13.0, 13.0, 12.0, 5.2 Hz, 1H, He4 ); 13C NMR5100 MHz,
00
0
CDCl3) d 200.1 5s, C3), 134.2 5d, C1 ), 126.8 5d, C2 ), 99.9
0
00
5s, C2), 82.4 5d, C2 ), 74.3 5d, C4a), 74.2 5d, C8a), 69.6
00
5d, C3 ), 68.3 5t, C6), 67.4 5t, C6 ), 50.1 5q, OCH3), 42.3 5t,
C4), 31.9 5t, C4 ), 31.0 5t, C8), 25.8 5t, C7), 25.1 5t, C5 ). Anal.
Calcd for C16H24O6: C, 61.52; H, 7.74. Found: C, 61.71; H,
7.76.
00
00
00
25
3:1); [a]D ˆ12.98 5c 0.61, CHCl3); IR5neat) 3020, 3012,
1729, 1283, 1092, 968 cm21; 1H NMR5400 MHz, CDCl 3) d
5.3.29. 14aR,5aS,6R,10aR,11aR,13aS)-11a-Methoxy-2,3,
4,4a,6,6a,8,9,10,10a,11a,13a-dodecahydro-1,5,7,11-tetra-
oxa-benzo[4,5]cyclohepta[1,2-b]naphthalen-5a-ol 158).
Colorless needle; mp 1308C; Rfˆ0.62 5hexane/EtOAc,
6.14 5d, Jˆ10.4 Hz, 1H, H3), 5.40 5dd, Jˆ10.4, 2.4 Hz, 1H,
0
H4), 4.03 5ddd, Jˆ11.7, 10.0, 4.5 Hz, 1H, H8 ), 3.90 5brd,
0
Jˆ11.0 Hz, 2H, He6, He6 ), 3.70 5brd, Jˆ8.6 Hz, 1H, H4a),
0
3.41±3.37 5m, 2H, Ha6, Ha6 ), 3.31±3.24 5m, 2H, H8a, H4 a),
0
25
0
9:1); [a]D ˆ18.28 5c 0.19, CHCl3); IR5KBr) 3470,
2.90 5dd, Jˆ14.0, 12.3 Hz, 1H, H4 ), 2.73 5dd, Jˆ14.0,
3011, 1560, 1094 cm21; H NMR5400 MHz, CDCl ) d
4.9 Hz, 1H, H4 ), 2.11 5brdd, Jˆ11.7, 4.5 Hz, 1H, He8 ),
1
0
0
3
5.86 5dd, Jˆ11.5, 2.0 Hz, 1H, H12), 5.44 5dd, Jˆ11.5,
2.0 Hz, 1H, H13), 4.08 5ddd, Jˆ9.8, 2.0, 2.0 Hz, 1H, H13a),
4.06 5ddd, Jˆ12.0, 3.0, 3.0 Hz, 1H, He8), 4.01 5ddd, Jˆ10.0,
9.0, 3.5 Hz, 1H, H6a), 3.88±3.82 5m, 2H, He2, H4a), 3.52
5ddd, Jˆ11.0, 9.0, 4.0 Hz, 1H, H10a), 3.42 5brdd, Jˆ12.0,
10.0 Hz, 1H, Ha8), 3.32±3.28 5m, 1H, Ha2), 3.28 5s, 3H,
CH3), 2.99 5dd, Jˆ14.0, 5.4 Hz, 1H, He6), 2.63 5dd, Jˆ
14.0, 10.0 Hz, 1H, Ha6), 2.18 5brdd, Jˆ14.0, 4.0 Hz, 1H,
He10), 2.06 5s, 1H, OH), 1.98±1.95 5m, 1H, He4), 1.84±
1.75 5m, 2H, 2£H9), 1.64±1.58 5m, 3H, 2£H3, Ha4), 1.60±
1.94 5brdd, Jˆ11.9, 4.5 Hz, 1H, He8), 1.76±1.60 5m, 4H,
0
2£H7 , 2£H7), 1.63 5dddd, Jˆ11.9, 11.1, 11.1, 5.9 Hz, 1H,
Ha8), 1.47 5dddd, Jˆ11.7, 11.7, 11.7, 5.5 Hz, 1H, Ha8 ); 13C
0
0
NMR5100 MHz, CDCl ) d 200.7 5s, C3 ), 134.1 5d, C3),
3
0
125.0 5d, C4), 97.5 5s, C2), 77.4 5d, C4 a), 74.8 5d, C4a),
0
74.3 5d, C8a), 69.9 5d, C8 a), 68.1 5t, C6), 67.6 5t, C6 ), 42.3
0
0
0
0
5t, C4 ), 28.9 5t, C8), 28.8 5t, C8 ), 25.3 5t, C7, C7 ). Anal.
Calcd for C15H20O5: C, 64.26; H, 7.20. Found: C, 64.43;
H, 7.29.
1.55 5m, 1H, Ha10); 13C NMR5100 MHz, CDCl ) d 141.0
5.3.32.
12R,4aS,8aR,40aR,80aS)-Spiro-12,4a,6,7,8,8a)-
3
5d, C13), 130.2 5d, C12), 101.0 5s, C11a), 95.2 5s, C5a), 79.5 5d,
C13a), 73.8 5d, C10a), 73.6 5d, C6a), 69.1 5t, C8), 68.1 5d, C4a),
67.8 5t, C2), 53.0 5q, OCH3), 38.7 5t, C6), 31.5 5t, C4), 31.2 5t,
C10), 26.0 5t, C9), 25.3 5t, C3). Anal. Calcd for C16H24O6: C,
61.52; H, 7.74. Found: C, 61.63; H, 7.80.
hexahydropyran[3,2-b]pyran-2-20-octahydropyran[3,2-b]-
pyran-30-one 162). Colorless oil; Rfˆ0.75 5hexane/EtOAc,
25
3:1); [a]D ˆ13.78 5c 0.46, CHCl3); IR5neat) 3025, 3014,
2950, 1740, 1283, 1118, 960 cm21; H NMR5400 MHz,
1
CDCl3) d 6.12 5d, Jˆ10.4 Hz, 1H, H3), 5.77 5dd, Jˆ10.4,
0
2.4 Hz, 1H, H4), 3.94±3.88 5m, 3H, H6, H6 , H4 a), 3.72 5ddd,
0
5.3.30. 14aR,5aS,6R,10aR,11aR,13aS)-5a,11a-Dimethoxy-
2,3,4,4a,6,6a,8,9,10,10a,11a,13a-dodecahydro-1,5,7,11-
tetraoxa-benzo[4,5]cyclohepta[1,2-b]naphthalene 159).
Prepared from 58 5110 mg, 0.35 mmol) following the
same procedure used to convert 44 to 45. Flash column
chromatography 5silica, 5% EtOAc in n-hexane) afforded
59 560.5 mg, 0.19 mmol, 53%). 59: colorless oil; Rfˆ0.64
Jˆ11.3, 9.0, 4.1 Hz, 1H, H8a), 3.58 5ddd, Jˆ9.0, 2.4, 1.8 Hz,
0
1H, H4a), 3.48 5ddd, Jˆ10.7, 10.7, 4.2 Hz, 1H, H8 a), 3.42±
0
0
3.36 5m, 2H, H6, H6 ), 3.04 5dd, Jˆ17.2, 6.4 Hz, 1H, H4 ),
0
2.39 5dd, Jˆ17.2, 10.9 Hz, 1H, H4 ), 2.18 5brdd, Jˆ12.2,
0
3.0 Hz, 1H, H8 ), 2.02 5brdd, Jˆ12.3, 3.4 Hz, 1H, He8),
13
0
1.77±1.73 5m, 4H, 2£H7, 2£H7 ), 1.59±1.53 5m, 2H, H8,
0
H8 ); C NMR5100 MHz, CDCl ) d 199.6 5s, C3 ), 134.2
0
3
25
0
5d, C3), 123.9 5d, C4), 96.8 5s, C2), 74.9 5d, C4a), 74.3 5d, C4 a,
5hexane/EtOAc, 4:1); [a]D ˆ110.58 5c 0.22, CHCl3); IR
5neat) 3016, 1603, 1342, 1112, 960 cm21; H NMR5400
1
0
C8 a), 70.7 5d, C8a), 68.3 5t, C6), 67.7 5t, C6 ), 42.2 5t, C4 ),
0
0
0
0
MHz, CDCl3) d 5.90 5dd, Jˆ12.0, 2.0 Hz, 1H, H12), 5.40
5dd, Jˆ12.0, 2.0 Hz, 1H, H13), 4.10 5ddd, Jˆ10.0, 2.0,
2.0 Hz, 1H, H13a), 4.06 5ddd, Jˆ14.0, 4.5, 4.5 Hz, 1H,
He8), 3.99 5ddd, Jˆ9.5, 9.5, 4.0 Hz, 1H, H6a), 3.90±3.81
5m, 2H, He2, H4a), 3.60 5ddd, Jˆ9.5, 9.0, 4.5 Hz, 1H,
H10a), 3.46 5brdd, Jˆ14.0, 13.0 Hz, 1H, Ha8), 3.41±3.36
5m, 1H, Ha2), 3.28 5s, 3H, CH3), 3.26 5s, 3H, OCH3), 3.25
5dd, Jˆ13.5, 4.0 Hz, 1H, He6), 2.74 5dd, Jˆ13.5, 9.5 Hz,
1H, Ha6), 2.40±2.36 5m, 1H, He10), 1.98±1.84 5m, 3H, 2£
H9, He4), 1.70±1.58 5m, 3H, 2£H3, Ha4), 1.56±1.48 5m, 1H,
Ha10); 13C NMR5100 MHz, CDCl 3) d 142.0 5d, C13), 133.3
5d, C12), 102.3 5s, C5a), 101.4 5s, C11a), 80.1 5d, C13a), 72.4 5d,
C10a), 72.4 5d, C6a), 70.3 5t, C8), 70.2 5d, C4a), 68.0 5t, C2),
54.3 5q, OCH3), 53.4 5q, OCH3), 41.0 5t, C6), 33.4 5t, C10),
33.1 5t, C4), 28.2 5t, C9), 26.0 5t, C3). Anal. Calcd for
C17H26O6: C, 62.56; H, 8.03. Found: C, 62.73; H, 8.12.
30.8 5t, C8 ), 28.9 5t, C8), 25.6 5t, C7), 25.3 5t, C7 ). Anal.
Calcd for C15H20O5: C, 64.26; H, 7.20. Found: C, 64.32; H,
7.45.
5.3.33. 12R,3S,20S,200R,400aS,800aR)-2-[20-1200,400a,600,700,800,
800a-Hexahydropyran[3,2-b]pyran-200-yl)-20-hydroxy-
ethyl]-tetrahydropyran-3-ol 163). To a solution of 57
5120 mg, 0.38 mmol) in freshly distilled CH3CN 55 mL) at
2308C were added Et3SiH 50.9 mL, 5.7 mmol) and then
BF3´OEt2 50.75 mL, 5.7 mmol). The resulting solution was
stirred for 12 h at 08C. The reaction mixture was then
diluted with ether 530 mL) and washed with saturated
NaHCO3 52£20 mL) and brine 52£20 mL). The organic
layer was dried 5MgSO4) and concentrated under vacuum.
Flash column chromatography 5silica, 30% EtOAc in
n-hexane) produced 63 572 mg, 0.25 mmol, 66%) and 64

M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
1939
00
4.1 Hz, 1H, H4 a), 2.13 5brs, 1H, D2O-exchangeable),
0 0 00 00
2.12±2.05 5m, 2H, H4 , H1 ), 2.04±1.98 5m, 2H, H8 , H4 ),
512 mg, 0.042 mmol, 11%). 63: colorless oil; Rfˆ0.55
5neat) 3483, 3013, 1463, 1439, 1328, 1091 cm21; 1H NMR
25
5hexane/EtOAc, 3:1); [a]D ˆ163.98 5c 0.93, CHCl3); IR
00
00
1.86 5brd, Jˆ12.9, 1H, H3 ), 1.68±160 5m, 5H, 2£H7 ,
2£H5, H3 ), 1.58±1.53 5m, 1H, H1 ), 1.48±1.40 5m, 3H,
H4, H4 , H8 ); 13C NMR5100 MHz, CDCl ) d 82.9 5d, C2),
00
00
0
5400 MHz, CDCl3) d 5.89 5d, Jˆ10.5 Hz, 1H, H3 ), 5.78
00
00
00
00
5dd, Jˆ10.5, 1.9 Hz, 1H, H4 ), 4.19 5brs, 1H, H2 ), 3.94±
3
00
0
00
00 00 00 0
80.2 5d, C2 ), 78.5 5d, C4 a), 78.1 5d, C8 a), 72.6 5d, C2 ), 70.0
00 0
5d, C3), 67.9 5t, C6 ), 67.7 5t, C6), 34.7 5t, C1 ), 32.4 5t, C4),
3.87 5m, 3H, He6 , He6, H2 ), 3.59 5brd, Jˆ8.3 Hz, 1H, H4 a),
00
3.45 5ddd, Jˆ11.4, 11.4, 4.3 Hz, 1H, Ha6 ), 3.39±3.33 5m,
00
2H, Ha6, H3), 3.28±3.23 5m, 2H, H2, H8 a), 2.10±2.06 5m,
00
29.7 5t, C8 ), 29.1 5t, C4 ), 25.7 5t, C3 ), 25.6 5t, C5), 25.6 5t,
00
00
00
00
00
0
00
C7 ). Anal. Calcd for C15H26O5: C, 62.91; H, 9.15. Found: C,
62.61; H, 9.0.
3H, He4, H1 , He8 ), 1.74±1.68 5m, 5H, 2£H5, 2£H7 , H1 ),
00
1.54 5dddd, Jˆ11.8, 11.8, 11.8, 5.4 Hz, 1H, Ha8 ), 1.40
5dddd, Jˆ12.1, 12.1, 11.0, 5.8 Hz, 1H, Ha4); 13C NMR
5.3.35. 12S,4aS,8aR,30S,40aR,80aS)-Spiro12,4a,6,7,8,8a)-
hexahydropyran[3,2-b]pyran-2,20-octahydropyran[3,2-b]-
pyran-30-ol 165). To a solution of spiroketone 61 550 mg,
0.18 mmol) in freshly distilled CH3CN 53 mL) at 2788C
were added Et3SiH 50.43 mL, 2.7 mmol) and then
BF3´OEt2 50.36 mL, 2.7 mmol). The resulting mixture was
stirred for 3 h at 2308C. The reaction was then diluted with
ether 515 mL) and washed with saturated NaHCO3
52£10 mL) and brine 52£10 mL). The organic layer was
dried 5MgSO4) and concentrated under vacuum. Flash
column chromatography 550±60% EtOAc in n-hexane)
produced 65 543 mg, 0.15 mmol, 83%). 65: colorless oil;
00
5100 MHz, CDCl3) d 129.2 5d, C3 ), 127.5 5d, C4 ), 80.7
00
00
00
5d, C2), 78.8 5d, C2 ), 75.6 5d, C4 a), 75.1 5d, C8 a), 72.7 5d,
00
0
C2 ), 70.0 5d, C3), 68.2 5t, C6 ), 67.7 5t, C6), 33.8 5t, C1 ), 32.4
00
0
1
5t, C4), 29.3 5t, C8 ), 25.8 5t, C5), 25.5 5t, C7 ); H NMR
00
00
00
00
5400 MHz, C6D6) d 6.08 5d, Jˆ11.0 Hz, 2H, H3 , H4 ),
00
4.24 5brs, 1H, H2 ), 4.05 5ddd, Jˆ9.3, 6.5, 2.3 Hz, 1H,
0
H2 ), 3.76 5brdd, Jˆ11.2, 4.7 Hz, 1H, He6), 3.63 5brd, Jˆ
00
00
8.2 Hz, 1H, H4 a), 3.55 5brdd, Jˆ11.2, 4.7 Hz, 1H, He6 ),
00
3.26±3.18 5m, 4H, H8 a, H2, H3, H6), 2.95 5ddd, Jˆ12.2,
00
11.2, 1.8 Hz, 1H, Ha6 ), 2.46 5ddd, Jˆ14.8, 2.3, 2.3 Hz,
0
00
1H, H1 ), 1.93 5brdd, Jˆ11.5, 3.0 Hz, 1H, He8 ), 1.86±
0
1.79 5m, 2H, Ha4, H1 ), 1.53 5ddddd, Jˆ13.0, 12.7, 12.2,
25
00
4.6, 4.1 Hz, 1H, Ha7 ), 1.44±1.39 5m, 2H, Ha8 , H5), 1.27
00
Rfˆ0.67 5EtOAc); [a]D ˆ12.78 5c 1.58, CHCl3); IR
5neat) 3599, 3017, 1468, 1223, 1042 cm21 1H NMR
;
00
5brd, Jˆ12.7 Hz, 1H, He7 ), 1.20±1.14 5m, 2H, He4, He5);
13
00
C NMR5100 MHz, C 6D6) d 128.2 5d, C3 ), 128.2 5d, C4 ),
00
5400 MHz, CDCl3) d 6.23 5d, Jˆ10.1 Hz, 1H, H3), 5.60
00
00
00
83.1 5d, C2), 79.1 5d, C2 ), 75.9 5d, C4 a), 75.3 5d, C8 a), 73.2
0
5d, C2 ), 69.9 5d, C3), 67.7 5t, C6 ), 67.3 5t, C6 ), 35.0 5t, C1 ),
00
32.5 5t, C4), 29.5 5t, C8 ), 25.8 5t, C7 ), 25.5 5t, C5). Anal.
Calcd for C15H24O5: C, 63.36; H, 8.51. Found: C, 63.31; H,
8.72. Diacetate: H NMR5400 MHz, CDCl ) d 5.89 5d,
5dd, Jˆ10.1, 2.1 Hz, 1H, H4), 3.92 5brd, Jˆ11.0 Hz, 1H,
0
00
0
0
He6), 3.88 5brd, Jˆ11.0 Hz, 1H, He6 ), 3.65±3.72 5m, 3H,
00
0
0
H4a, H3 , H8 a), 3.43 5ddd, Jˆ11.0, 9.5, 5.0 Hz, 1H, Ha6),
3.40±3.37 5m, 1H, H8a), 3.36 5ddd, Jˆ11.0, 11.0, 4.0 Hz,
1
0
0
1H, Ha6 ), 2.98 5ddd, Jˆ11.6, 9.4, 4.2 Hz, 1H, H4 a), 2.18±
3
00
0 0
2.12 5m, 2H, H8, H4 ), 2.00±1.93 5m, 1H, H8 ), 1.89±1.83
Jˆ10.4 Hz, 1H, H3 ), 5.66 5ddd, Jˆ10.4, 2.2, 2.2 Hz, 1H,
00
0
0
0
H4 ), 5.11 5ddd, Jˆ8.2, 4.2, 4.2 Hz, 1H, H2 ), 4.44 5ddd,
5m, 1H, H4 ), 1.81±1.70 5m, 4H, 2£H7, 2£H7 ), 1.62±1.54
5m, 1H, H8), 1.40±1.32 5m, 1H, H8 ); 13C NMR5100 MHz,
CDCl3) d 135.6 5d, C3), 128.1 5d, C4), 96.3 5s, C2), 76.9 5d,
00
0
Jˆ10.4, 10.4, 5.0 Hz, 1H, H3), 4.35 5brs, 1H, H2 ), 3.94
00
5ddd, Jˆ11.0, 2.0, 2.0 Hz, 1H, He6 ), 3.85 5ddd, Jˆ11.4,
00
0 0 0
C4 a), 76.5 5d, C4a), 74.7 5d, C8a), 72.6 5d, C3 ), 69.7 5t, C8 a),
0 0
68.2 5t, C6 ), 67.9 5t, C6), 33.9 5t, C4 ), 29.2 5t, C8), 29.1 5t,
2.8, 2.8 Hz, 1H, He6), 3.55 5brd, Jˆ8.2 Hz, 1H, H4 a),
0
3.45 5ddd, Jˆ11.0, 11.0, 4.0 Hz, 1H, Ha6 ), 3.36 5ddd,
0
0
Jˆ12.0, 10.4, 4.2 Hz, 1H, H2), 3.28 5ddd, Jˆ11.4, 11.4,
2.8 Hz, 1H, Ha6), 3.20 5ddd, Jˆ11.0, 8.2, 4.0 Hz, 1H,
C8 ), 25.6 5t, C7), 25.5 5t, C7 ). Anal. Calcd for C15H22O5: C,
63.81; H, 7.85. Found: C, 63.63; H, 7.82. Compound 65
538 mg, 0.13 mmol) under the same conditions used to
convert 57 to the mixture 63 and 64, gave diols 63
516 mg, 0.056 mmol) and 64 58 mg, 0.028 mmol) in 67%
overall yield.
00
H8 a), 2.15 5brdd, Jˆ12.0, 3.3 Hz, 1H, He4), 2.09±2.00
00
5m, 7H, He8 , 2£CH3CO2), 1.94 5ddd, Jˆ15.0, 4.2, 4.2 Hz,
0
00
0
1H, H1 ), 1.78±1.70 5m, 3H, 2£H7 , H1 ), 1.68±1.62 5m, 2H,
2£H5), 1.51 5dddd, Jˆ12.0, 11.7, 11.7, 5.6 Hz, 1H, Ha4),
1.38 5dddd, Jˆ12.4, 10.8, 10.8, 4.6 Hz, 1H, Ha8 ); 13C NMR
0
5100 MHz, CDCl3) d 170.6 5s, CH3CO2), 170.1 5s,
5.3.36. 12R,4aS,8aR,30S,40aR,80aS)-Spiro12,4a,6,7,8,8a)-
hexahydropyran[3,2-b]pyran-2,20-octahydropyran[3,2-b]-
pyran-30-ol 166). Prepared from 62 550 mg, 0.18 mmol)
following the same procedure to convert 61 to 65. Flash
column chromatography 5silica, 50±60% EtOAc in
n-hexane) gave 66 536 mg, 0.13 mmol, 72%). 66: colorless
00
00
CH3CO2), 129.5 5d, C3 ), 127.0 5d, C4 ), 77.3 5d, C2), 76.7
00
5d, C2 ), 75.4 5d, C4 a), 75.1 5d, C8 a), 72.9 5d, C2 ), 72.0 5d,
00
C3), 68.2 5t, C6 ), 67.4 5t, C6), 31.7 5t, C1 ), 29.3 5t, C8 ), 29.3
00
5t, C4), 25.7 5t, C7 ), 24.9 5t, C5), 21.3 5q), 21.2 5q).
Hemiacetal 58 5110 mg, 0.32 mmol), following the earlier
described conditions gave 63 569 mg, 0.24 mmol, 75%) and
64 57 mg, 0.03 mmol, 9%).
00
00
0
0
00
25
oil; Rfˆ0.57 5EtOAc); [a]D ˆ213.38 5c 0.44, CHCl3); IR
5neat) 3600, 3013, 1468, 1356, 1014 cm21 1H NMR
;
5400 MHz, CDCl3) d 6.22 5dd, Jˆ10.7, 1.6 Hz, 1H, H4),
5.3.34. 12R,3S,20S,200R,400aS,800)-2-[20-Octahydropyran-
[3,2-b]pyran-200-yl-20-hydroxyethyl]-tetrahydropyran-3-
ol 164). Colorless oil; Rfˆ0.44 5hexane/EtOAc, 3:1);
6.19 5d, Jˆ10.7 Hz, 1H, H3), 3.97 5brdd, Jˆ11.5, 4.5 Hz,
0
1H, He6), 3.92 5brdd, Jˆ14.1, 1.8 Hz, 1H, He6 ), 3.82 5ddd,
Jˆ11.5, 9.1, 4.1 Hz, 1H, H8a), 3.68 5dd, Jˆ12.3, 4.7 Hz, 1H,
25
0
[a]D ˆ166.28 5c 0.18, CHCl3); IR5neat) 3502, 3156,
H3 ), 3.61 5d, Jˆ9.1 Hz, 1H, H4a), 3.46 5ddd, Jˆ11.5, 11.5,
2858, 1464, 1380, 990 cm21; H NMR5400 MHz, CDCl )
3.5 Hz, 1H, Ha6), 3.40±3.36 5m, 1H, Ha6 ), 3.27 5ddd, Jˆ
1
0
3
00
0
d 3.89±3.83 5m, 2H, He6 , He6), 3.84 5ddd, Jˆ5.2, 5.2,
10.8, 9.3, 4.8 Hz, 1H, H8 a), 3.12 5ddd, Jˆ11.6, 9.3, 4.4 Hz,
0
1.6 Hz, 1H, H2 ), 3.70 5brs, 1H, D2O-exchangeable), 3.43±
0
0
1H, H4 a), 2.28 5ddd, Jˆ12.3, 4.7, 4.4 Hz, 1H, He4 ), 2.10
00
3.35 5m, 3H, Ha6 , H3, Ha6), 3.28 5ddd, Jˆ9.4, 9.4, 5.2 Hz,
5brdd, Jˆ12.3, 4.1 Hz, 1H, He8), 2.00 5brdd, Jˆ12.0,
00
0
0
0
1H, H2 ), 3.24 5ddd, Jˆ9.0, 9.0, 3.0 Hz, 1H, H2), 3.05 5ddd,
4.8 Hz, 1H, He8 ), 1.80±1.68 5m, 5H, Ha4 , 2£H7, 2£H7 ),
00
0
Jˆ8.8, 8.8, 2.7 Hz, 1H, H8 a), 2.95 5ddd, Jˆ10.9, 8.8,
1.66±1.62 5m, 1H, Ha8), 1.59±1.53 5m, 1H, Ha8 ); 13C NMR

1940
M. L. Candenas et al. / Tetrahedron 58 22002) 1921±1942
USA 1997, 94, 1527±1532. 5k) Diss, J. K.; Stewart, D.; Fraser,
S. P.; Black, J. A.; Dib-Hajj, S.; Waxman, S. G.; Archer, S. N.;
Djamgoz, M. B. FEBS Lett. 1998, 427, 5±10.
5100 MHz, CDCl3) d 134.5 5d, C3), 122.8 5d, C4), 98.7 5s,
0
C2), 76.9 5d, C4 a), 75.9 5d, C4a), 73.1 5d, C8 a), 71.9 5d, C3 ),
0
0
0
0
70.9 5t, C8a), 68.4 5t, C6), 68.0 5t, C6 ), 33.9 5t, C4 ), 29.7 5t,
0
0
4. 5a) Rojas, C. V.; Wang, J. Z.; Schwartz, L. S.; Hoffman, E. P.;
Powell, B. R.; Brown Jr., R. H. Nature 1991, 354, 387±389.
5b) McClatchey, A. I.; Van den Bergh, P.; Pericak-Vance,
M. A.; Raskind, W.; Verellen, C.; McKenna-Yasek, D.;
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George Jr., A. L. Nature 1995, 376, 683±685. 5d) Chen, Q.;
Kirsch, G. E.; Zhang, D.; Brugada, R.; Brugada, J.; Brugada,
P.; Potenza, D.; Moya, A.; Borggrefe, M.; Breithardt, G.;
Ortiz-Lopez, R.; Wang, Z.; Antzelevitch, C.; O'Brien, R. E.;
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C8 ), 28.9 5t, C8), 25.6 5t, C7 ), 25.4 5t, C7). Anal. Calcd for
C15H22O5: C, 63.81; H, 7.85. Found: C, 63.83; H, 7.90.
Compound 66 531 mg, 0.11 mmol) under the conditions
used to convert 57 to the mixture 63 and 64, afforded 63
514 mg, 0.05 mmol, 45%) and 64 56 mg, 0.02 mmol, 18%).
A 1:1 mixture of compounds 65 and 66 is quantitatively
formed by base hydrolysis of 55 5MeONa cat./MeOH/
258C/30 min) followed by acid induced 5BF3´OEt2/
CH3CN/2308C/15 min) spirocyclization of the resulting
diol.
Acknowledgements
We are grateful to Professor K. Nakanishi and Dr M. L.
Souto, Columbia University, for providing BTX-2 5BTX-
B) and to Professor T. Yasumoto and Dr M. Satake, Tohoku
University, for a sample of PbTx-3. This work was
supported by grants from the Ministry of Science and
Technology 5BQU2001-1137) and Fundacion Ramon
Areces. R. L. P. thanks AECI, Spain, for a fellowship. C.
G. C. thanks the MEC, Spain, for a Predoctoral fellowship.
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Â
Â
Â
Â
Candenas, M. L.; Perez, R.; Ravelo, J.-L.; Martõn, J. D.
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