Synthesis and cation complexation properties of new macrolides

Article abstract of DOI:10.1016/j.tet.2005.06.034

The cis-2-alkyl-3-oxy-tetrahydropyran unit as a novel structure for the design and synthesis of a new type of ionophores with C₂-symmetry is reported. The synthesis of seven different macrolides and a crown ether and their cation complexation p

Full text of DOI:10.1016/j.tet.2005.06.034

Tetrahedron 61 (2005) 8177–8191
Synthesis and cation complexation properties of new macrolides
†
Romen Carrillo, Victor S. Martın, Matıas Lopez and Tomas Martın
*
´
´
´
´
´
´ ´ ´ ´
Instituto Universitario de Bio-Organica ‘Antonio Gonzalez’, Universidad de La Laguna, C/Astrofısico Francisco Sanchez,
2, 38206 La Laguna, Tenerife, Spain
Received 18 April 2005; revised 10 June 2005; accepted 13 June 2005
Available online 7 July 2005
Abstract—The cis-2-alkyl-3-oxy-tetrahydropyran unit as a novel structure for the design and synthesis of a new type of ionophores with C2-
symmetry is reported. The synthesis of seven different macrolides and a crown ether and their cation complexation properties were
investigated. The X-ray crystal structure of some of the receptors provides valuable information on the preferred conformation of
tetrahydropyrans in the solid state that can be related to the cation complexation properties in solution. The kinetic template effect has been
proved to be a useful tool to improve the yield and selectivity in the synthesis of macrodiolide 3.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently, reported that cis-2-alkyl-3-oxy-
tetrahydropyran can be used as a privileged structural unit
for the design of new C2-symmetry macrodiolides with
cation complexation properties.9 In this article, we report
full details of this design concept employed in the synthesis
of seven macrolides and a crown ether. In addition, the
evaluation of their complexation properties is fully
discussed.
A wide range of biological processes such as the generation
and propagation of the electrical impulse in the nervous
system, muscular contraction, the production and storage of
energy and cellular communication require the interactions
of proteins and enzymes with cations. Therefore, the search
for simple models that allow us the molecular understanding
of these phenomena is of particular importance. Cation
receptors have been used in selective complexation, as
detectors, in selective transport, catalysis, etc. Over the last
30 years, a great number of functional groups have been
incorporated into the design of new cation receptors.
Tetrahydropyrans are widespread in nature1,2,3 and syn-
thetic ionophores.4,5 This structural unit confers more
rigidity and new properties to the systems in which it is
present, and it is for that reason that tetrahydropyrans have
been used as building blocks in cation recognition. Thus,
mention can be made of chorand-type cyclooligolides
designed and synthesized by Okada6 and Burke.7 On the
other hand, Still et al. designed and synthesized a podand-
type system of linked tetrahydropyran rings whose
conformation is controlled by the presence of methyl
groups at C-3.8 However, all these receptors have in
common the use of tetrahydropyran rings linked through
positions C-2 and C-6, where the tetrahydropyran oxygen
participates in the recognition process.
The 2-alkyl-3-oxy-tetrahydropyran unit is widely displayed
in polyether toxins of marine origin, and is usually found in
trans disposition. This configuration directs the two oxygens
toward the opposed faces, generating a practically flat
system, which may not be well adapted for cation
recognition (Fig. 1).10 Alternatively, the cis configuration
can preferredly be found in two conformations, one with the
3-oxy group axial (A), with both oxygens located on the
same face, and the other one equatorial (B), forcing both
oxygens to be located on opposite faces, the first of these
Keywords: Macrolides; Ionophores; Template effect.
*
Corresponding author. Tel.: C34 922 318580; fax: C34 922 318571;
e-mail: tmartin@ull.es
† Any questions related to X-ray crystallography should be addressed to
mlopez@ull.es
Figure 1. Trans- and cis-2-alkyl-3-oxy-tetrahydropyran units and main
conformers.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.034

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R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
Figure 2. Design and structures of macrodiolides 1, 2, 3 and 4 and crown ether 6 based on 2-alkyl-3-oxy-tetrahydropyran units.
being the one that may generate the suitable curvature, such
that both oxygens can participate in the recognition.
designed the tricyclic diolides 1, 2, 3, structurally
characterized by the presence of two cis-2-alkyl-3-oxy-
tetrahydropyran units, linked by two carbonyl, two oxo-
methylene and two 2-oxy-acetyl groups as spacers, forming
a 10-, 12-, and 14-membered macrodiolide, respectively.
Using the same design, and in order to check the importance
of the configuration of the 2-alkyl-3-oxy-tetrahydropyran
moieties, we decided to synthesize compound 4, which
displays the trans fusion. In addition, we prepared the crown
ether 6, to verify the influence of the carbonyl groups in
cation recognition.
On the other hand, it is well known that the best and easiest
way to maintain the chirality of a unit is by transforming this
into a molecule with C2 symmetry. To accomplish this, we
linked the oxy group of a unit with the alkyl group of the
other, using identical spacers (Fig. 2). A desirable property
for such spacers is that they must be reasonably flexible to
allow the participation of the tetrahydropyran oxygen in the
recognition. Also, they must allow the easy synthesis of the
receptor. Moreover, the existence of additional heteroatoms,
susceptible to acting as ligands, may also be positive.
Finally, the presence in nature of a great number of
bioactive macrodiolides, such as the fattiviracins,11 cyclo-
varicins,12 nactins,13 or pamamycin-60714 was considered.
With these ideas in mind, a series of macrodiolides of
different sizes and different degrees of oxygenation, having
different carbon-based spacers, were synthesized. Thus, we
In principle, these structures could be considered formally
to be bibracchial lariat ethers (BiBLE), where the central
macroring is a formal crown ether and the tetrahydropyran
rings are the side-arms that confer greater conformational
rigidity and whose oxygens could participate in the
complexation. From modelling,15 it can be predicted that
the cis fusion could create a hydrophilic concave face where
Figure 3. Molecules 1, 2, 3 and 6 in the suitable conformation such that cation recognition may take place (U-shaped) and low-energy conformation of trans-
macrodiolide 4.

R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
8179
(Scheme 2), the diol 1116 was protected, as the bis-silyl
ethers, followed by selective deprotection of the silyl ether
of the primary alcohol to afford the cis-alcohol 14, which
can be considered the key piece in the synthesis of the
receptors. Thus, to obtain the precursor of compound 1, one-
carbon homologation of the cis-alcohol 14 to the carboxylic
acid 16 was performed by a simple four-step sequence:
oxidation to aldehyde by Swern reaction, Wittig methylena-
tion (Ph3P]CH2) to afford alkene 15, hydroboration with
9-BBNH in THF, and oxidative cleavage of the alkyl
borane, yielding the primary alcohol, which was oxidated to
the corresponding carboxylic acid 16. Esterification of the
carboxylic acid 16 with benzyl alcohol and further
Scheme 1. Retrosynthetic analysis for macrodiolides 1, 2, 3 and 4.
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2; (b) TFA:THF:H2O (1:1:1); (c) (COCl)2, DMSO, CH2Cl2, then Et3N; (d) Ph3P]CH2,
THF; (e) (i) 9-BBN, THF; (ii) H2O2, NaOH; (f) NaIO4, RuCl3 (cat.), CH3CN: CCl4: H2O (2:2:3); (g) BnOH, DMAP, CSA, DCC, CH2Cl2; (h) HF, CH3CN;
(i) Ph3PCHCO2CH3, C6H6; (j) LiOH, THF, H2O, D; (k) NaH, ICH2CO2Na, THF; (l) H2, Pd(OH)2, AcOEt; (m) (CH3O)2POCH2CO2Bn, NaH, C6H6.
the oxygen atoms act as ligands wrapping the cation guest,
and a hydrophobic convex face where the carbon skeleton is
oriented to the outer surface. On the other hand, the trans
fusion shows a practically flat structure (Fig. 3).
deprotection of the tert-butyl-dimethylsilyl (TBS) ether
afforded the hydroxy ester 17.
The synthesis of the precursor of the macrodiolide 3 was
carried out from alcohol 14 by alkylation with sodium
iodoacetate to provide the carboxylic acid 18, then applying
the same sequence of reactions as before to obtain
compound 17, afforded the hydroxy ester 19. The synthesis
of free hydroxy-acids 8 and 10 was performed by a simple
catalytic hydrogenation of the benzyl esters 17 and 19,
respectively.
Additionally, we synthesized the central 14-membered
macrodiolide 5 and 14-crown-4(7) to verify that metal
complexation in the macrodiolides 3 and 4 and crown ether
6 does not take place in the macrocyclic plane.
Macrodiolides 1, 2, and 3 were envisioned as being
synthesized from two units of a suitable cis-hydroxy-acid,
where the spacers are: carbonyl (8), oxo-methylene (9) and
2-oxy-acetyl (10) groups, respectively, by an intermolecular
esterification followed by macrolactonization (Scheme 1).
Tetrahydropyrans 8, 9 and 10 could be obtained from
commercially available tri-O-acetyl-D-galactal. Similar
retrosynthetic analysis for the trans-macrodiolide 4 leads
to the use of commercially available tri-O-acetyl-D-glucal as
starting material.
Disappointingly, the direct dimerization approach, under all
assayed conditions, of the hydroxy acids 8 and 10, is
2. Results and discussion
2.1. Synthesis of macrolides
Scheme 3. Reagents and conditions: (a) 2-chloro-1,3-dimethylimidazo-
linium chloride, NaH or KH, DMAP in CH2Cl2, 0 8C/rt; (b) 2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, CH2Cl2 (0.1 M).
To carry out the synthesis of the hydroxy acids 8 and 10

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R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
Scheme 4. Reagents and conditions: (a) DMAP, CSA, DCC, CH2Cl2; (b) HF, CH3CN; (c) H2, Pd(OH)2, AcOEt; (d) PySSPy, Ph3P, toluene, D; (e) 2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, CH2Cl2.
entropically unfavourable, affording the lactonization
product 2017 and 21, respectively, even using conditions
that have been described as excellent to obtain macro-
diolides, such as 2-chloro-1,3-dimethylimidazolinium
chloride in the presence of DMAP and NaH or KH in
CH2Cl2 (Scheme 3).18
Finally, for the synthesis of macrodiolides 1, 2 and 3 a
convergent strategy was applied: iterative esterification
couplings of two suitably functionalized tetrahydropyran
units, carboxylic acid 16 and alcohol 17 for macrodiolide 1,
carboxylic acid 23 and alcohol 26 for macrodiolide 2 or
carboxylic acid 18 and alcohol 19 for macrodiolide 3,
followed by macrolactonization of the resulting hydroxy-
acid. Therefore, to carry out the synthesis of compound 1, a
coupling of the carboxylic acid 16 with the hydroxy ester 17
was achieved affording pseudodimer 27 (Scheme 4). Then,
cleavage of the alcohol protecting group gave the hydroxy
ester 28. Catalytic hydrogenation of the benzyl ester 28
provided the hydroxy-acid, which was transformed into the
phenylthioester and submitted to Corey macrolactonization
conditions,20 affording the g-lactone 20 along with the
macrodiolide 1, in 2:1 proportion, respectively. To perform
the synthesis of compound 2, the same sequence of reaction
used to obtain macrodiolide 1 was applied, using the
(E)-a,b-unsaturated acid 23 and the alcohol 26 (Scheme 4),
this last compound being prepared from alcohol 14 by a
simple three-step sequence: Swern oxidation to the
aldehyde, treated with the sodium salt of benzyl dimethyl-
phosphonoacetate and deprotection of the silyl ether
(Scheme 2).
To overcome this difficulty, alternative synthetic strategies
were developed. Thus, in the case of the macrodiolide 2, a
trans double bond could be placed at the a,b position of the
acid group in 9, with which, we avoided the first
intramolecular lactonization taking place, only the inter-
molecular esterification being allowed, followed by a
macrolactonization in the same process.
To perform the synthesis of the precursor of compound 2,
two-carbon homologation of the cis-alcohol 14 was
achieved (Scheme 2), using a Swern oxidation and a Wittig
reaction of the aldehyde with the stabilized phosphorane
Ph3P]CHCO2Me in benzene, affording the methyl
(E)-a,b-unsaturated ester 22, which was converted into the
(E)-a,b-unsaturated acid 24, by saponification of the methyl
ester and deprotection of the TBS group. Unfortunately, all
attempts (DCC, DMAP; 2-chloro-1,3-dimethylimidazo-
linium chloride, NaH, DMAP) to carry out the synthesis
of the macrodiolide 2 via dimerization of the (E)-a,b-
unsaturated acid 24 and further catalytic hydrogenation
were unfruitful. Surprisingly, when the (E)-a,b-unsaturated
acid 24 was treated under modified Yamaguchi conditions19
the (Z)-a,b-unsaturated d-lactone 25 was the only observed
product as the result of concomitant isomerization of the
double bond and lactonization (Scheme 3).
To achieve the synthesis of compound 3, the same sequence
of reactions used to obtain 27 was applied, using the
carboxylic acid 18 and alcohol 19, obtaining the hydroxy
ester 31 (Scheme 5). Catalytic hydrogenation of 31 afforded
the hydroxy-acid 32, which was transformed into the
thioester 33. Unfortunately, 33 under Corey macrolactoni-
zation conditions gave exclusively the macrotetraolide 34.
However, when compound 32 was treated under Yamaguchi
conditions, the macrodiolide 3 was obtained in 20% yield
along with macrotetraolide 34 in 40% yield.21 However, the
kinetic template effect improved selectivity and yield in the
macrolactonization (vide infra).
Using the diol 1322 and applying the same sequence of
reactions described above, under Yamaguchi conditions in
the cyclization step, we obtained the macrodiolide 4 and the
macrotetraolide 35 (trans-isomer of 34) (Scheme 6), in 55
and 35% yields, respectively. The same strategy was applied
to obtain compound 5, using as starting material 3-{[tert-
butyl(dimethyl)silyl]oxy}-1-propanol. Nevertheless, in this
case, when we used Yamaguchi conditions in the
macrolactonization step, we obtained exclusively macro-
tetrolide 40. Fortunately, using Corey conditions, macro-
diolide 5 was the only formed compound.
Scheme 5. Reagents and conditions: (a) DMAP, CSA, DCC, CH2Cl2;
(b) HF, CH3CN, 0 8C; (c) H2, Pd(OH)2, AcOEt; (d) PySSPy, Ph3P, CH2Cl2;
(e) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, THF (0.01 M)/toluene
(0.001 M), D; (f) toluene (0.001 M), D.

R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
8181
Scheme 6. Reagents and conditions: (a) (i) TBSCl, imidazole, CH2Cl2; (ii) TFA: THF: H2O (1:1:1); (b) NaH, ICH2CO2Na, THF; (c) (i) BnOH, DCC, DMAP,
CSA, CH2Cl2; (ii) HF, MeCN; (d) H2, Pd(OH)2, AcOEt; (e) DCC, DMAP, CSA, CH2Cl2; (f) HF, MeCN; (g) Et3N, 2,4,6-trichlorobenzoyl chloride, THF
(0.01 M)/toluene (0.001 M), DMAP, D; (h) PySSPy, Ph3P, THF (0.3 M)/toluene (0.01 M), D; (i) Et3N, 2,4,6-trichlorobenzoyl chloride, THF (0.02 M)/
toluene (0.002 M), DMAP.
of 40 with 2-chloroethyl tetrahydro-2H-pyran-2-yl ether
yielded compound 42,23 which was used as a common
precursor. With 42 in hand we prepared the secondary
alcohol 43 by cleavage of the benzyl protecting group under
hydrogenation conditions. In parallel, compound 42 was
transformed to tosylate 44, by cleavage of the tetra-
hydropyranyl group under acid conditions and subsequent
reaction with tosyl chloride under basic conditions.24 We
next turned our attention to the critical convergent coupling
step of the two fragments 43 and 44, which was achieved
with sodium hydride in refluxing THF and further
deprotection of the tetrahydropyranyl group under acid
conditions, affording compound 45 in excellent yield. The
alcohol 45 was converted into the tosylate 46, which under
hydrogenation conditions provided the secondary alcohol
47. Finally, the intramolecular ether formation was carried
out with sodium hydride in THF at rt to afford the crown
ether 6, in good yield. In this case we did not observe the
formation of cyclic ethers having a larger ring size, probably
due to a NaC kinetic template effect.
Scheme 7. Reagents and conditions: (a) PhCH(OCH3)2, CSA (cat.),
CH2Cl2; (b) DIBAL-H, CH2Cl2; (c) ClCH2CH2OTHP, Bu4NHSO4,
NaOH(aqueous), 65 8C; (d) HCl (cat.), MeOH; (e) TsCl, KOH(aqueous),
THF; (f) H2, Pd(OH)2, AcOEt; (g) NaH, THF, 0 8C/D; (h) NaH, THF, rt.
The crown ether 6 was synthesized by a divergent–
convergent strategy, using the diol 11 that was protected
as the benzylidene acetal and subsequently submitted to
reductive cleavage, affording the benzyl ether 41 in good
yield (Scheme 7). The O-alkylation of the primary alcohol
The 14-crown-4(7) was synthesized in accordance with the
literature method.25 The structures of the macrodiolides 1, 2,
3, 4 and 5, the crown ether 6 and the macrotetrolides 34 and
Table 1. Association constants Ka (MK1) with different cationsa
Entry
Host
LiC
NaC
KC
NHC4
CsC
b
b
b
b
b
1
2
3
4
5
6
7
8
9
1
2
3
4
5
34
—
—
—
—
—
b
b
b
b
b
—
4.6!103
—
—
2.5!104
—
—
1.6!104
—
—
2.0!103
—
—
2.0!103
—
b
b
b
b
b
b
b
b
b
b
—
—
—
—
—
b
—
b
—
b
—
b
—
b
—
b
b
b
b
35
6
14-crown-4(7)
—
2.3!103
3.1!105
—
7.1!103
6.7!103
2.3!103
6.2!103
4.7!102
—
9.6!102
2.4!102
—
1.1!103
2.8!102
a These values are the average of three independent measurements.
b — means that these values were smaller than 102.

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R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
35 were unambiguously determined by NMR spectroscopy
constant values and with the minimized structures shown in
Figure 3. Host 3 wraps the metal cation and can change the
cavity size according to the metal cation size, such that it
shows comparable binding ability to all alkali metal cations.
Interestingly, in macrotetrolides the result is reversed, trans
being better than cis, perhaps as a result of folding of
compound 35 over the KC.
(1H and 13C) and FAB mass spectrometry.26
2.2. Cation complexation studies
The association constants (Ka) of the macrodiolides 1, 2, 3, 4
and 5, the macrotetraolides 34, 35 and the ethers 6 and 7 in
CHCl3 saturated with water at 23–25 8C were determined by
measurements from the CHCl3 layer using Cram’s picrate
extraction method (Table 1).27,28 The absorption maxima in
CHCl3 (352!lmax!359 nm) of the picrate salts are
indicative of 1:1 complexes between metal picrate and the
host.29 The results of Table 1 show that the substrates 3 and
6 display moderate association constants (entries 3 and 8),
and the macrodiolide 3 is slightly specific for NaC and KC
(NaC/LiCZ5.4, KC/LiCZ3.5).
In addition, we observed that the conformation of the
tetrahydropyrans of compound 3 is the same before and
after the complexation. In the free receptor, the NOE effects
(CDCl3) indicate that a large number of molecules have the
tetrahydropyran rings in the A conformation (Fig. 1),
implying a partially pre-organized system. Thus, when one
deals with potassium thiocyanate and ultrasound, to form
the complex 3$KC (CDCl3),30 the NOE effects continue as
before, although changes take place in the chemical shift of
the signals in the proton and carbon NMR spectra.26 This,
along with the value of the association constant, allows us to
conclude that almost all the molecules adopt the U-shaped
conformation in the complex (Fig. 3), and that the change in
the chemical shift must be mainly due to the change in
conformation of the flexible part of the molecule, that is to
say, the 14-membered macrocycle.
It should be emphasized that the 2,3 relative configuration
of the tetrahydropyrans is critical to achieve cation
recognition, since the trans-isomer (macrodiolide 4) is
completely ineffective in the extraction process (entry 4).
This observation implies that the cis-tetrahydropyran
oxygen participates in the recognition process and this
along with the null complexation observed by macrodiolide
5 (entry 5) allows us to conclude that the complexation in 3
takes place out of the macrodiolide plane, like a clamp-type
rather than a chorand-type ionophore, despite the fact that 3
is a macrocycle. This is in agreement with the association
Considering the great difference in the values of the
association constants between macrodiolide 5 and the
14-crown-4(7) (entry 9, Table 1), we expected that crown
Figure 4. Crystal structures of compounds 1, 4, 6, 34 and 35.

R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
8183
ether 6 would show better association constants than
macrodiolide 3, since when eliminating the carbonyl
groups, which withdraw electronic density from esters
oxygen, these oxygens would have a greater contribution in
the cations complexation. Surprisingly, we observed a
decrease in the association constants (entry 8, Table 1). This
fact leads us to believe that although those carbonyl groups
produce an unfavourable electronic factor, they confer
greater rigidity to the molecule, favouring the suitable
conformation for the complexation process. Furthermore,
the crystal structure of 6 (Fig. 4) revealed that the
tetrahydropyrans have the right conformation for complexa-
tion (conformation A, Fig. 1), but the absence of the
carbonyl groups causes the central part of this molecule to
be quite flexible, preventing good cation recognition.31
C2 symmetry that could recognize small cations, despite the
enormous size of the macrocycle (28 members). This fact
could explain the association constant observed with KC
(entry 7, Table 1).
2.3. Template effect studies
In light of the low yields obtained in the macrolactonization
process in the synthesis of macrodiolide 3, and considering
the association constants observed for 3 and 34, we decided
to explore the possible template effect that could be exerted
by metallic cations in the cyclization step. In our first
attempt we explored the possibility to perform a covalent
self-assembly33 using the methyl ester 48,34 under similar
conditions to those employed by Sanders and co-workers
(Scheme 8).35 We even tried to perform a thermodynamic
templated synthesis, using the methyl ester 4936 with
MeONa or MeOK. However, all attempts were unfruitful,
affording only the lactone 21 and traces of macrotetraolide
34.
In contrast, it was observed that the association constants of
the small macrodiolides 1 and 2 were smaller (entries 1 and
2, Table 1). A possible explanation may be that the absence
of additional oxygens is critical for the complexation. Also,
it is possible that the conformation of the tetrahydropyrans
is not suitable. Thus, in solid phase, the crystal structure of 1
(Fig. 4)32 has an inadequate B type conformation (Fig. 1) for
the complexation, whereas, in CDCl3 solution, NOE
experiments demonstrate that a mixture of conformers
exists. Probably, the experimental result reflects the
combination of both facts and the deficiency of ligands
makes the conversion more expensive towards the A
conformation, perhaps because of an insufficient enthalpy
change. In contrast, the crystal structure of the macro-
tetrolide 34 (Fig. 4) revealed a molecule with a pseudo-
quaternary symmetry, where the tetrahydropyran rings are
in the right conformation for the complexation process.
Although the association constants were poor (entry 6,
Table 1) as a result of the large cavity that this compound
displays. As predicted, the crystal structure of 4 (Fig. 4)
practically shows a flat molecule, unsuitable for the cation
recognition. Nevertheless, the crystal structure of the trans-
macrotetrolide 35 (Fig. 4) revealed a folded molecule with a
Scheme 8.
Next, we explored a kinetic template effect, using 2-chloro-
1,3-dimethylimidazolinium chloride in the presence of
DMAP and Et3N or NaH or KH in CH2Cl2 (entries 1–3,
Table 2), affording, in moderate yield, the macrotetraolide
34.
Having in mind that using the standard Yamaguchi
conditions we were able to obtain compound 3 (entry 4,
Table 2), albeit with low selectivity, the following step was
the addition of an alkali metal cation under such conditions.
Since this did not improve yield and selectivity, we
Table 2. Template effect study in the cyclization of 32 and 33
Entry
Substrate
Reagentsa
Solvent (M)
Additive
(equiv)
Temp.
(8C)
Time
Yieldb
(%)
3:34
1
2
3
4
5
6
7
8
32
32
32
32
32
32
32
33
33
33
33
33
33
33
33
33
33
Et3N, DCIC, DMAP
NaH, DCIC, DMAP
KH, DCIC, DMAP
Et3N, TCBC, DMAPc
NaH, TCBC, DMAP
NaH, TCBC, DMAP
Et3N, TCBCd
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
PPh3, PySSPy
CH2Cl2 (0.01)
CH2Cl2 (0.01)
CH2Cl2 (0.01)
Toluene (0.001)
THF (0.01)
CH2Cl2 (0.01)
CH2Cl2 (0.002)
Toluene (0.001)
CH2Cl2 (0.002)
CH2Cl2 (0.002)
CH2Cl2 (0.002)
CH2Cl2 (0.002)
CH2Cl2 (0.002)
CH2Cl2 (0.002)
CH2Cl2 (0.002)
THF (0.002)
—
—
—
—
—
—
rt
rt
rt
reflux
rt
rt
rt
reflux
reflux
reflux
rt
16 h
16 h
16 h
6 h
12 h
12 h
22 h
1 day
7 days
1d
55
47
43
60
48
50
65
50
—
—
65
50
55
95
—
25
—
0:100
0:100
0:100
33:67
0:100
40:60
87:13
0:100
—
K2CO3 (20)
—
—
Et3N (2)
DMAP (2)
Li2CO3 (20)
9
10
11
12
13
14
15
16
17
—
1 h
0:100
50:50
65:35
87:13
—
reflux
9 days
9 days
7 days
12 h
1 day
1 day
Na2CO3 (20) reflux
K2CO3 (20)
Cs2CO3 (20)
K2CO3 (20)
KI (20)
reflux
reflux
rt
0:100
—
CH2Cl2 (0.002)
reflux
a DCIC, 2-chloro-1,3-dimethylimidazolinium chloride; TCBC, 2,4,6-trichlorobenzoyl chloride; PySSPy, 2,20-dipyridyl disulfide.
b Yields corresponding to compounds 3C34.
c Et3N (2 equiv), 2,4,6-trichlorobenzoyl chloride (1.3 equiv) in THF (0.01 M), then was diluted with toluene (0.001 M) and poured over DMAP (10 equiv) in
boiling toluene.
d Et3N (2 equiv), 2,4,6-trichlorobenzoyl chloride (1.3 equiv) in CH2Cl2 (0.01 M), then was diluted with CH2Cl2 (0.002 M) and K2CO3 (20 equiv) was added
and the mixture was warmed up to reflux.

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R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
pondered the influence of the solvent. Thus, although using
NaH in THF afforded only compound 34 (entry 5, Table 2),
in dichloromethane selectivity was slightly improved (entry
6, Table 2). The use of K2CO3 enhanced selectivity, but in
these conditions the reaction was difficult to reproduce
(entry 7, Table 2). Then we decided to explore the
macrolactonization using a stable intermediate, thioester
33, allowing the cyclization step to proceed slowly and in
consequence increasing the template effect. Corey con-
ditions (in toluene) afforded macrotetrolide 34 (entry 8,
Table 2). When using boiling dichloromethane as solvent, it
is noteworthy that no cyclization product was detected
(entry 9, Table 2). It seems that, due to the low boiling point
of dichloromethane, the addition of a base becomes
necessary. Nevertheless, the presence of triethylamine to
activate the attack of the hydroxyl group was unfruitful
(entry 10, Table 2). On the contrary, the presence of DMAP
increased the rate of the reaction, but, unfortunately, toward
the formation of macrotetrolide 34 (entry 11, Table 2). After
several trials (entries 12–17, Table 2), we found that better
selectivity and yields of compound 3 versus 34 were
achieved in boiling dichloromethane with potassium
carbonate, where the KC acts as a template (entry 14,
Table 2), pre-organizing the cyclization precursor for
macrolactonization (Fig. 5), favouring the formation of 3
(95% yield, 3/34Z6.7).
4. Experimental
4.1. Materials and methods
1H NMR spectra were recorded at 400 and 300 MHz, 13C
NMR spectra were recorded at 75 MHz, and chemical shifts
are reported relative to internal Me4Si. Optical rotations
were determined for solutions in chloroform. Column
˚
chromatography was performed on silica gel, 60 A and 0.
2–0.5 mm. Compounds were visualized by use of UV light,
2.5% phosphomolybdic acid in ethanol or vanillin with
acetic and sulfuric acid in ethanol with heating. All solvents
were purified by standard techniques.37 Reactions requiring
anhydrous conditions were performed under nitrogen.
Anhydrous magnesium sulfate was used for drying
solutions.
4.1.1. Preparation of [(2R,3R)-3-(tert-butyldimethylsilyl-
oxy)-tetrahydro-2H-pyran-2-yl]methanol (14). tert-
Butylchlorodiphenylsilane (12.9 g, 85.3 mmol) was added
in one portion to a cold (0 8C) and stirred solution of diol 11
(4.5 g, 34.1 mmol) and imidazole (5.8 g, 85.3 mmol) in dry
CH2Cl2 (70 mL, 0.5 M) under nitrogen atmosphere. The
reaction mixture was stirred at reflux for 20 h before dilution
with MeOH and Et2O. The mixture was washed with an
aqueous saturated NH4Cl solution, water and brine and then
dried, filtered and concentrated to yield the crude bis-silyl
ether as an oil which was used without further purification.
Trifluoroacetic acid (35 mL) was added dropwise to a
solution of the crude bis-silyl ether in THF (35 mL) and
water (35 mL) at 0 8C. After stirring for 5 min, the reaction
mixture was quenched with (NaHCO3, 25 g), diluted with
ether, washed with water and brine and then dried. The
solvent was removed by vacuum and the residue was
purified by chromatography on silica gel to give alcohol 14
(7.15 g, 85% yield) as an oil: [a]2D5K2.9 (c 2.1, CHCl3); 1H
NMR (CDCl3) d 0.06 (s, 6H), 0.89 (s, 9H), 1.34 (d, JZ
13.3 Hz, 1H), 1.62 (dddd, JZ2.7, 2.7, 13.3, 13.3 Hz, 1H),
1.80 (ddd, JZ1.8, 1.8, 13.6 Hz, 1H), 1.90–2.10 (m, 1H),
2.25 (br s, 1H), 3.39–3.56 (m, 3H), 3.77 (dd, JZ8.5,
11.2 Hz, 2H), 3.98 (dddd, JZ2.1, 2.1, 11.3, 11.3 Hz, 1H);
13C NMR (CDCl3) dK5.0 (q), K4.6 (q), 18.0 (s), 20.6 (t),
25.7 (q), 31.1 (t), 63.8 (t), 66.5 (d), 67.6 (t), 79.9 (d); IR
(CHCl3) (cmK1) 3427, 2951, 2886, 2856, 1463, 1254,
1101; MS m/z (relative intensity) 247 (MCH)C (100), 189
(MKBu-t)C (7), 137 (46). HRMS calcd for C12H27O3Si
(MCH)C: 247.1729, found: 247.1732.
Figure 5. Template effect in the macrolactonization step.
To the best of our knowledge, this is the first time that the
Corey macrolactonization reaction is used under alkali
metal cation template effect. It should be emphasized that
the best guest (NaC) for host 3 is not the best template for its
formation. This may be due to the fact that the cavity size of
the transition state leading to compound 3 is slightly larger
than the cavity of the final product.
3. Conclusions
We have used the cis-2-alkyl-3-oxy-tetrahydropyran as a
new structural unit for the design of ionophores. Hosts 3 and
6 behave like a clamp-type ionophore, where the recog-
nition takes place out of the macrocyclic plane, with
assistance of the cis-tetrahydrofuran oxygen. The carbonyl
groups in the macrodiolide 3 help to confer a greater rigidity
to the molecule, favouring the suitable conformation for the
complexation process. The X-ray crystal structure of
compounds 1, 4, 6, 34 and 35 provides valuable information
in the solid state that supports their cation complexation
properties in solution. The template effect has been proven
to be a useful tool to improve the yield and selectivity in the
synthesis of macrodiolide 3. In addition, this structural unit
can be used to obtain new receptors, by simply changing the
design or nature and length of the spacers.
4.1.2. Preparation of tert-butyl(dimethyl)silyl(2R,3R)-2-
vinyltetrahydro-2H-pyran-3-yl ether (15). To a solution
of the oxalyl chloride (0.79 mL, 9 mmol) in dry CH2Cl2
(30 mL) under argon at K78 8C was added DMSO
(0.86 mL, 12 mmol). After 15 min of stirring, a solution
of 14 (1.5 g, 6 mmol) in dry CH2Cl2 (3 mL) was added.
After 1 h, Et3N (3.35 mL, 24 mmol) was added and the
reaction was allowed to warm to rt. The reaction was diluted
with CH2Cl2 and washed with a HCl aqueous solution (5%
w/v), a saturated aqueous solution of NaHCO3 and brine,
dried over MgSO4 and concentrated. The crude obtained
was filtered through a pad of silica gel and the aldehyde was
used in the next reaction.

R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
8185
A solution of n-BuLi (4.1 mL of a 1.75 M solution in
hexane, 7.2 mmol) was added dropwise via syringe to a
stirred and ice-cooled suspension of methyltriphenyl-
phosphonium bromide (2.79 g, 7.8 mmol) in anhydrous
THF (45 mL) under argon. After 15 min, the crude aldehyde
dissolved in THF (5 mL) was added. The resulting mixture
was stirred for 2 h and then quenched with a saturated
aqueous solution of NH4Cl and diluted with Et2O. The
aqueous layer was extracted with Et2O and the combined
organic layers were dried (MgSO4), filtered, concentrated
and purified by silica gel flash-chromatography, yielding 15
(1.28 g, 88% yield) as an oil: [a]2D5C1.1 (c 1.1, CHCl3); 1H
NMR (CDCl3) d 0.04 (s, 6H), 0.90 (s, 9H), 1.35 (ddd, JZ
2.7, 2.7, 13.2 Hz, 1H), 1.63–1.70 (m, 1H), 1.78–1.84 (m,
1H), 1.92–2.08 (m, 1H), 3.49 (ddd, JZ2.5, 11.3, 11.3 Hz,
1H), 3.73 (s, 1H), 3.83 (d, JZ6.2 Hz, 1H), 3.99 (d, JZ
11.3 Hz, 1H), 5.17 (dd, JZ1.3, 10.6 Hz, 1H), 5.25 (dd, JZ
1.3, 17.2 Hz, 1H), 5.91 (ddd, JZ6.3, 10.6, 17.2 Hz, 1H);
13C NMR (CDCl3) dK5.0 (q), K4.6 (q), 18.2 (s), 20.7 (t),
25.9 (q), 31.1 (t), 67.1 (t), 68.6 (d), 81.1 (d), 116.2 (t), 137.0
(d); IR (film) (cmK1) 3019, 2927, 2855, 1216; MS m/z
(relative intensity) 185 (MKBu-t)C(13), 97 (19), 85 (50),
71 (73), 57 (100). HRMS calcd for C9H17O2Si (MKBu-t)C:
185.0998, found: 185.1000.
the acid 16 (0.6 g, 2.2 mmol) in dry CH2Cl2 (22 mL) under
argon were added sequentially with stirring DMAP (0.35 g,
2.9 mmol), benzyl alcohol (0.27 mL, 2.6 mmol) and
camphorsulfonic acid (151 mg, 0.7 mmol) at rt. The mixture
was stirred for 15 min, and DCC (0.59 g, 2.9 mmol) was
slowly added. The reaction mixture was additionally stirred
for 3 h, then, it was diluted in CH2Cl2 (10 mL), filtered
through a pad of Celite and washed with a 5% (w/v) HC1
aqueous solution, a saturated aqueous solution of NaHCO3
and saturated brine. The organic phase was dried over
MgSO4, concentrated, and purified by chromatography on
silica gel, to afford the benzyl ester (650 mg, 85% yield) as
an oil: [a]2D5C1.3 (c 1.8, CHCl3); 1H NMR (CDCl3) d 0.018
(s, 3H), 0.048 (s, 3H), 0.91 (s, 9H), 1.32 (d, JZ13.2 Hz,
1H), 1.601.72 (m, 1H), 1.80–1.86 (m, 1H), 1.90–2.08 (m,
1H), 2.52 (dd, JZ5.6, 16.0 Hz, 1H), 2.67 (dd, JZ7.7,
16.0 Hz, 1H), 3.47 (ddd, JZ2.3, 11.4, 11.4 Hz, 1H), 3.75 (s,
1H), 3.84 (dd, JZ4.2, 4.2 Hz, 1H), 3.92 (dd, JZ1.9, 9.5 Hz,
1H), 5.13 (dd, JZ12.4, 16 Hz, 2H), 7.30–7.35 (m, 5H); 13C
NMR (CDCl3) dK5.0 (q), K4.6 (q), 18.1 (s), 20.4 (t), 25.8
(q), 30.9 (t), 37.0 (t), 66.2 (t), 66.9 (d), 67.6 (t), 76.3 (d),
128.1 (d), 128.2 (d), 128.5 (d), 136.0 (s), 171.6 (s); IR (film)
(cmK1) 3034, 2952, 2856, 1737; MS m/z (relative intensity)
307 (MKBu-t)C(40), 101 (10), 91 (100), 73 (13). HRMS
calcd for C16H23O4Si (MKBu-t)C: 307.1366, found:
307.1351.
4.1.3. Preparation of 2-[(2R,3R)-3-(tert-butyldimethyl-
silyloxy)-tetrahydro-2H-pyran-2-yl]acetic acid (16). To a
stirred solution of 15 (1.28 g, 5.3 mmol) in dry THF (50 mL,
0.1 M) under argon at 0 8C was added dropwise the
9-borabicyclo[3.3.1]nonane (15.9 mL, 7.9 mmol). The
reaction was allowed to warm slowly to rt and stirred
additionally for 12 h until TLC showed the end of the
reaction. The reaction mixture was cooled to 0 8C and H2O2
(30% w/v, 2.8 mL), NaOH (3 M, 1.2 mL) and H2O (1.2 mL)
were added sequentially with stirring. The mixture was
allowed to warm to rt and stirred. After 0.5 h the mixture
was extracted with ether and the combined organic solutions
were washed with brine, dried, evaporated in vacuo and the
residue was used without further purification.
To a solution of the benzyl ester (646 mg, 1.8 mmol) in
CH3CN (17 mL) at 0 8C was added HF (48%, 0.9 mL) and
the reaction was stirred for 1 h. Then, the mixture was
diluted with Et2O (15 mL) and washed with saturated
NaHCO3 (aqueous). The aqueous layer was extracted with
Et2O and the combined organic layers were dried (MgSO4),
filtered and concentrated. Silica gel column chromato-
graphy of the residue gave alcohol 17 (290 mg, 65% yield)
as a white solid: mp 67–68 8C: [a]2D5C1.6 (c 0.9, CHCl3);
1H NMR (CDCl3) d 1.41 (d, JZ12.8 Hz, 1H), 1.63–1.69 (m,
1H), 1.83–1.90 (m, 2H), 2.60 (dd, JZ5.6, 15.8 Hz, 1H),
2.70 (dd, JZ7.8, 15.9 Hz, 1H), 3.49 (ddd, JZ1.3, 11.8,
11.8 Hz, 1H), 3.68 (s, 1H), 3.85 (dd, JZ5.9, 7.0 Hz, 1H),
3.96 (dd, JZ3.0, 11.5 Hz, 1H), 5.14 (dd, JZ12.4, 15.7 Hz,
2H), 7.26–7.38 (m, 5H); 13C NMR (CDCl3) d 19.8 (t), 30.4
(t), 37.3 (t), 66.3 (d), 66.3 (t), 68.3 (t), 76.4 (d), 128.0 (d),
To a solution of the crude in CH3CN (14 mL), CCl4
(14 mL), H2O (21 mL) were added NaIO4 (4.5 g, 21.
2 mmol) and a catalytic amount of RuCl3$xH2O. The
reaction mixture was vigorously stirred until TLC showed
complete conversion to the acid 16. The reaction was
diluted with Et2O, MgSO4 was added and the mixture was
filtered through a pad of Celite and concentrated. Silica gel
column chromatography of the residue gave acid 16 (1.28 g,
88% yield) as a white solid: mp 73–76 8C: [a]2D5C3.2 (c 1.0,
CHCl3); 1H NMR (CDCl3) d 0.06 (s, 6H), 0.91 (s, 9H), 1.35
(d, JZ13.4 Hz, 1H), 1.66 (dd, JZ13.6, 13.6 Hz, 1H), 1.81–
1.87 (m, 1H), 1.90–2.08 (m, 1H), 2.49 (dd, JZ5.0, 16 Hz,
1H), 2.67 (dd, JZ8.1, 16 Hz, 1H), 3.49 (dd, JZ11.4,
11.4 Hz, 1H), 3.73 (s, 1H), 3.79 (dd, JZ5.0, 8.0 Hz, 1H),
3.96 (d, JZ11.3 Hz, 1H); 13C NMR (CDCl3) d 5.0 (q),
K4.6 (q), 18.1 (s), 20.2 (t), 25.8 (q), 30.7 (t), 36.9 (t), 67.0
(d), 67.7 (t), 76.1 (d), 176.2 (s); IR (film) (cmK1) 3020,
2929, 2856, 1216; MS m/z (relative intensity) 217 (MKBu-
t)C (30), 97 (39), 83 (49), 75 (100). HRMS calcd for
C9H17O4Si (MKBu-t)C: 217.0896, found: 217.0925.
128.1 (d), 128.5 (d), 135.9 (s), 171.4 (s); IR (film) (cmK1
)
3450, 2943, 2854, 1734; MS m/z (relative intensity) 250
(M)C (0.25), 232 (4), 143 (5), 91 (43), 71 (100). HRMS
calcd for C14H18O4 (M)C: 250.1205, found: 250.1195.
4.1.5. Preparation of 2-{[(2R,3R)-3-(tert-butyldimethyl-
silyloxy)-tetrahydro-2H-pyran-2-yl]methoxy}acetic acid
(18). To a solution of alcohol 14 (2 g, 8.1 mmol) in dry THF
(81 mL) and under nitrogen were added sodium iodoacetate
(1.69 g, 8.1 mmol) and NaH (715 mg, 17.9 mmol, 60% oil
dispersion) at 0 8C. The reaction was allowed to warm to rt
and stirred overnight. The reaction was diluted with water
and the pH was adjusted to 4 with a HCl aqueous solution
(5% w/v). The aqueous layer was saturated with solid NaCl
and extracted with EtOAc. The extracts were dried over
MgSO4, filtered and concentrated. The crude residue was
purified by flash chromatography over silica gel using 1:9
MeOH: CH2Cl2 to yield acid 18 (2.33 g, 94% yield) as an
oil: [a]2D5K3.2 (c 1.5, CHCl3); 1H NMR (CDCl3) d 0.02 (s,
3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.35 (d, JZ13.6 Hz, 1H),
4.1.4. Preparation of benzyl 2-((2R,3R)-3-hydroxy-tetra-
hydro-2H-pyran-2-yl)acetate (17). To a stirred solution of

8186
R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
1.61–1.66 (m, 1H), 1.79–1.80 (m, 1H), 1.95–2.08 (m, 1H),
3.44 (ddd, JZ1.9, 10.1, 10.1 Hz, 1H), 3.60–3.63 (m, 2H),
3.69–3.71 (m, 1H), 3.75 (s, 1H), 4.03 (ddd, JZ2.4, 2.4,
11.6 Hz, 1H), 4.09 (d, JZ16.4 Hz, 1H), 4.17 (d, JZ
16.4 Hz, 1H), 7.41 (br s, 1H); 13C NMR (CDCl3) dK5.1 (q),
K4.6 (q), 18.1 (s), 20.2 (t), 25.7 (q), 30.9 (t), 65.7 (d), 67.7
compound 15 was applied to 14 on a 554 mg (2.3 mmol)
scale, using in the Wittig step methyl (triphenyl-
phosphoranylidene) acetate in dry benzene, yielding 22
(625 mg, 92% yield) as a colourless oil: [a]2D5C1.1 (c 1.5,
1
CHCl3); H NMR (CDCl3) d 0.003 (s, 3H), 0.04 (s, 3H),
0.87 (s, 9H), 1.38 (d, JZ13.4 Hz, 1H), 1.69–1.73 (m, 1H),
1.79–1.85 (m, 1H) 1.96–2.04 (m, 1H), 3.50 (ddd, JZ2.6,
11.1, 11.1 Hz, 1H), 3.73 (s, 3H), 3.82–3.84 (m, 1H), 3.97–
4.05 (m, 2H), 6.06 (dd, JZ1.8, 15.8 Hz, 1H), 6.90 (dd, JZ
4.4, 15.8 Hz, 1H); 13C NMR (CDCl3) dK5.0 (q), K4.5 (q),
18.1 (s), 20.7 (t), 25.7 (q), 31.1 (t), 51.4 (q), 67.0 (t), 67.8
(t), 69.1 (t), 73.6 (t), 78.6 (d), 173.3 (s); IR (film) (cmK1
)
3422, 2925, 2855, 1733, 1090; MS m/z (relative intensity)
305 (MCH)C (0.3), 247 (MKBu-t)C (4), 189 (39), 171
(16), 133 (96), 105 (41), 97 (100), 75 (80). HRMS calcd for
C24H29O5Si (MCH)C: 305.1784, found: 305.1778.
(d), 78.7 (d), 121.3 (d), 146.6 (d), 166.8 (s); IR (film) (cmK1
)
2956, 2857, 1726, 1305, 1262; MS m/z (relative intensity)
299 (MKH)C(8), 243 (31), 187 (60), 113 (65), 75 (100).
HRMS calcd for C15H27O4Si (MKH)C: 299.1678, found:
299.1665.
4.1.6. Preparation of benzyl 2-{[(2R,3R)-3-hydroxy-
tetrahydro-2H-pyran-2-yl]methoxy}acetate (19). To a
stirred solution of the acid 18 (1.5 g, 4.9 mmol) in dry
CH2Cl2 (49 mL) under argon were sequentially added with
stirring DMAP (787 mg, 6.4 mmol), benzyl alcohol
(664 mg, 6.4 mmol) and camphorsulfonic acid (344 mg,
1.5 mmol) at rt. The mixture was stirred for 15 min, and
DCC (1.32 g, 6.4 mmol) was slowly added and the mixture
was additionally stirred for 3 h, and diluted in CH2Cl2,
filtered through a pad of Celite and washed with a 5% (w/v)
HC1 aqueous solution, a saturated aqueous solution of
NaHCO3 and saturated brine. The organic phase was dried
over MgSO4, concentrated, and purified by chromatography
on silica gel, to afford the benzyl ester (1.85 g, 95% yield):
4.1.8. Preparation of (2E)-3-[(3S,2R)-3-{[tert-butyl-
(dimethyl)silyl]oxy}tetrahydro-2H-pyran-2-yl)prop-2-
enoic acid (23). To a solution of the methyl ester 22
(625 mg, 2.1 mmol) in THF (3 mL) and H2O (1.8 mL) was
added LiOH$H2O (251 mg, 6.3 mmol) and the mixture was
stirred at reflux for 5 h, after which time TLC showed that
the starting material had disappeared. Then a 3 M solution
of HCl was added at 0 8C until pHz5 was reached. The
reaction mixture was diluted with Et2O and washed with
H2O and brine. The organic phase was dried over MgSO4,
concentrated, and the residue was purified by chromato-
graphy on silica gel, to afford the acid 23 (560 mg, 94%
yield) as a white solid: mp 101–104 8C: [a]2D5C1.9 (c 1.2,
CHCl3); 1H NMR (CDCl3) d 0.01 (s, 3H), 0.04 (s, 3H), 0.87
(s, 9H), 1.38 (m, 1H), 1.69–1.85 (m, 2H), 1.95–2.05 (m,
1H), 3.51 (ddd, JZ2.5, 11.1, 11.1 Hz, 1H), 3.85 (s, 1H),
3.99–4.13 (m, 2H), 6.07 (dd, JZ1.6, 15.8 Hz, 1H), 6.99 (dd,
JZ4.1, 15.8 Hz, 1H); 13C NMR (CDCl3) dK4.9 (q), K4.7
(q), 18.1 (s), 20.6 (t), 25.7 (q), 31.2 (t), 67.1 (t), 67.7 (d),
1
[a]2D5K14.6 (c 1.1, CHCl3); H NMR (CDCl3) d 0.02 (s,
3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.31 (d, JZ13 Hz, 1H),
1.55–1.66 (m, 1H), 1.78–1.83 (m, 1H), 1.97–2.05 (m, 1H),
3.44 (ddd, JZ2.2, 11.6, 11.6 Hz, 1H), 3.58–3.65 (m, 3H),
3.78 (s, 1H), 3.96 (ddd, JZ2.1, 2.1, 11.3 Hz, 1H), 4.12 (d,
JZ16.5 Hz, 1H), 4.21 (d, JZ16.5 Hz, 1H), 5.18 (s, 2H),
7.35 (m, 5H); 13C NMR (CDCl3) dK5.0 (q), K4.6 (q), 18.1
(s), 20.4 (t), 25.8 (q), 31.0 (t), 65.9 (d), 66.4 (t), 67.6 (t), 72.5
(t), 78.8 (d), 128.3 (d), 128.6 (d), 170.3 (s); IR (film) (cmK1
)
2951, 2855, 2362, 1758, 1135; MS m/z (relative intensity)
417 (MCNa)C (17), 395 (MCH)C(34), 337 (MKBu-t)C
(18), 227 (8), 136 (9), 91 (100), 73 (27). HRMS calcd for
C21H34O5Na1Si (MCNa)C: 417.2073, found: 417.2094.
78.7 (d), 121.0 (d), 149.0 (d), 171.4 (s); IR (film) (cmK1
)
2953, 2857, 1699, 1257, 1023; MS m/z (relative intensity)
229 (MKBu-t)C (92), 211 (37), 185 (35), 137 (38), 75
(100). HRMS calcd for C10H17O4Si (MKBu-t)C: 229.0896,
found: 229.0892.
To a solution of the benzyl ester (995 mg, 2.5 mmol) in
CH3CN (25 mL) at 0 8C, was added HF (48%, 1.3 mL) and
the reaction was stirred for 3–4 h. Then, the mixture was
diluted with Et2O and washed with saturated aqueous
NaHCO3. The aqueous layer was extracted with Et2O and
the combined organic layers were dried (MgSO4), filtered
and concentrated. Silica gel column chromatography of the
residue gave alcohol 19 (692 mg, 98% yield) as an oil:
4.1.9. Preparation of unsaturated d-lactone 25. To a
solution of the acid 23 (120 mg, 0.4 mmol) in CH3CN
(3.8 mL) at 0 8C was added HF (48%, 0.4 mL) and the
reaction was stirred for 5 h. Then, the mixture was diluted
with Et2O, MgSO4 was added, the mixture was filtered and
concentrated and the crude residue was used without further
purification.
1
[a]2D5K14.9 (c 1.4, CHCl3); H NMR (CDCl3) d 1.35–1.40
(m, 1H), 1.55–1.70 (m,1H), 1.93–2.05 (m, 2H), 3.50–3.55
(m, 1H), 3.68 (dd, JZ2.4, 5.6 Hz, 2H), 3.87 (s, 1H), 3.99
(ddd, JZ2.3, 2.3, 11.2 Hz, 1H), 4.11 (d, JZ16.8 Hz, 1H),
4.15 (d, JZ16.8 Hz, 1H), 5.18 (dd, JZ12.5 Hz, 2H), 7.31–
7.38 (m, 5H); 13C NMR (CDCl3) d 20.1 (t), 30.0 (t), 65.3 (d),
66.8 (t), 68.4 (t), 68.5 (t), 72.1 (t), 78.0 (d), 128.5 (d), 128.5
(d), 128.6 (d), 170.7 (s); IR (film) (cmK1) 3479, 2944, 2853,
1752, 1213, 1132; MS m/z (relative intensity) 303 (MC
Na)C(7), 281 (MCH)C(44), 91 (100). HRMS calcd for
C15H20O5Na1 (MCNa)C: 303.1208, found: 303.1242.
To a solution of the hydroxy acid in dry CH2Cl2 (4.2 mL, 0.
1 M) at 0 8C under nitrogen atmosphere were added Et3N
(87 mL, 0.6 mmol) and DMAP (103 mg, 4.2 mmol). The
mixture was stirred for 10 min at 0 8C and 2,4,6-
trichlorobenzoyl chloride (98 mL, 0.6 mmol) was added
and the reaction was allowed to warm to rt. The reaction
mixture was diluted in CH2Cl2, washed with a 5% (w/v)
HC1 aqueous solution, a saturated aqueous solution of
NaHCO3 and saturated brine. The organic phase was dried
over MgSO4, concentrated, and purified by chromatography
on silica gel, to afford the unsaturated d-lactone 25 (27 mg,
42% overall yield) as a white solid: mp 48–49 8C: [a]2D5K
77.7 (c 1.5, CHCl3); 1H NMR (CDCl3) d 1.46–1.51 (m, 2H),
4.1.7. Preparation of methyl (2E)-3-((2R,3R)-3-{[tert-
butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-2-yl)-2-
propenoate (22). The same procedure used above to obtain

R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
8187
1.77–1.88 (m, 2H), 1.93–2.04 (m, 2H) 2.20–2.27 (m, 2H),
3.50 (ddd, JZ2.2, 11.6, 11.6 Hz, 2H), 3.90–4.07 (m, 4H),
4.34 (s, 2H), 6.17 (d, JZ9.6 Hz, 2H), 6.87 (dd, JZ5.9,
9.6 Hz, 2H); 13C NMR (CDCl3) d 19.9 (t), 27.2 (t), 66.6 (d),
67.4 (t), 73.1 (d), 124.6 (d), 141.7 (d), 163.9 (s); IR (film)
(cmK1) 2930, 1715, 1252, 1090; MS (FAB) m/z (relative
intensity) 155 (MCH)C(100), 154 (M)C(23), 95 (24), 69
(52), 54 (56).
stirred for 3–4 h. Then, the mixture was diluted with Et2O
and washed with a saturated aqueous solution of NaHCO3.
The aqueous layer was extracted with Et2O and the
combined organic layers were dried (MgSO4), filtered and
concentrated. Silica gel column chromatography of the
residue gave benzyl ester 28 (200 mg, 96% yield) as an oil:
1
[a]2D5K7.4 (c 1.1, CHCl3); H NMR (CDCl3) d 1.36–1.39
(m, 2H), 1.70–2.00 (m, 6H), 2.44 (dd, JZ5.0, 15.9 Hz, 1H),
2.52–2.71 (m, 3H), 3.47 (dd, JZ2.0, 11.6, 11.6, 11.6,
11.6 Hz, 2H), 3.62 (s, 1H), 3.80–3.83 (m, 1H), 3.91–3.99
(m, 3H), 4.90 (s, 1H), 5.07 (d, JZ12.4 Hz, 1H), 5.12 (d, JZ
12.4 Hz, 2H), 7.27–7.34 (m, 5H); 13C NMR (CDCl3) d 19.7
(t), 20.3 (t), 27.7 (t), 30.3 (t), 37.1 (t), 37.5 (t), 66.2 (d), 66.3
(t), 68.0 (t), 68.2 (t), 68.6 (d), 74.6 (d), 76.4 (d), 128.0 (d),
128.1 (d), 128.4 (d), 137.7 (s), 170.7 (s), 170.8 (s); IR (film)
(cmK1) 3452, 2950, 2855, 1734; MS (FAB) m/z (relative
intensity) 393 (MCH)C (8), 307 (7), 154 (47), 136 (37), 91
(100). HRMS (FAB) calcd for C21H29O7 (MCH)C:
393.1913, found: 393.1891.
4.1.10. Preparation of benzyl (2E)-3-[(2R,3R)-tetra-
hydro-3-hydroxy-2H-pyran-2-yl]-2-propenoate (26).
The same procedure used above to obtain compound 22
was applied to 14 on a 600 mg (2.4 mmol) scale, using in the
Wittig–Horner step the sodium salt of benzyl dimethyl-
phosphonoacetate in dry benzene and followed by deprotec-
tion of the silyl ether with HF in CH3CN, yielding 26
(525 mg, 82% yield) as a white solid: mp 114–117 8C:
[a]2D5K19.6 (c 0.75, CHCl3); H NMR (CDCl3) d 1.42 (m,
1
1H), 1.73 (m, 1H), 1.89–2.04 (m, 2H), 3.52 (ddd, JZ2.3,
11.9, 11.9 Hz, 1H), 3.83 (s, 1H), 4.02–4.08 (m, 2H), 5.18 (s,
2H), 6.17 (dd, JZ2.0, 15.7 Hz, 1H), 6.92 (dd, JZ2.0,
15.7 Hz, 1H), 7.35 (m, 5H); 13C NMR (CDCl3) d 19.8 (t),
30.2 (t), 66.3 (t), 66.5 (d), 68.3 (t), 78.6 (d), 122.0 (d), 128.1
(d), 128.2 (d), 128.5 (d), 136.0 (q), 145.7 (d), 166.0 (s);
MS m/z (relative intensity) 171 (MKBn)C (6), 146 (18),
88 (39), 71 (54), 57 (100). HRMS calcd for C8H11O4
(MKBn)C: 171.0657, found: 171.0658.
4.1.13. Preparation of macrolide 1. A mixture of the
benzyl ester 28 (200 mg, 0.5 mmol) and Pd(OH)2 (10 mg) in
EtOAc (5.1 mL) was placed under H2 atmosphere. The
reaction mixture was vigorously stirred until TLC showed
complete conversion to the hydroxyl acid. The mixture was
filtered through a pad of Celite. The solvent was removed
under reduced pressure and the residue was used without
further purification.
4.1.11. Preparation of (2R,3R)-2-[2-(benzyloxy)-2-
oxoethyl]tetrahydro-2H-pyran-3-yl ((2R,3R)-3-{[tert-
butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-2-yl)
acetate (27). To a stirred solution of the acid 16 (150 mg,
0.6 mmol) in dry CH2Cl2 (3 mL) under argon were added
sequentially with stirring DMAP (87 mg, 0.7 mmol),
alcohol 17 (137 mg, 0.6 mmol) and camphorsulfonic acid
(38 mg, 0.2 mmol) at rt. The mixture was stirred for 15 min,
and DCC (147 mg, 0.7 mmol) was slowly added. The
reaction mixture was additionally stirred for 5 h and diluted
in CH2Cl2, filtered through a pad of Celite and washed with
a 5% (w/v) HC1 aqueous solution, a saturated aqueous
solution of NaHCO3 and saturated brine. The organic phase
was dried over MgSO4, concentrated, and purified by
chromatography on silica gel, to afford the benzyl ester 27
To a mixture of hydroxyl acid and 2,20-dipyridyl disulfide
(145 mg, 0.7 mmol) in dry toluene (1.8 mL) at rt was added
triphenylphosphine (175 mg, 0.7 mmol) in one portion. The
reaction mixture was stirred for 6 h prior to diluting with dry
toluene (55 mL, 0.01 M) and then the mixture was refluxed
overnight. The solvent was removed under vacuum and the
residue was purified by chromatography on silica gel, to
yield macrodiolide 1 (36 mg, 25% yield) and g-lactone 20
(36 mg, 50% yield). Macrodiolide 1: white solid: mp 130–
1
133 8C: [a]2D5C9.2 (c 1.4, CHCl3); H NMR (CDCl3) d
1.51–1.53 (m, 2H), 1.82–1.96 (m, 6H), 2.66 (dd, JZ5.3,
13.3 Hz, 2H), 2.82 (dd, JZ8.2, 13.3 Hz, 2H), 3.50–3.55 (m,
2H), 3.79–3.84 (m, 2H), 4.05–4.09 (m, 2H), 4.86–4.89 (m,
2H); 13C NMR (CDCl3) d 21.7 (t), 26.6 (t), 37.7 (t), 65.9 (t),
69.5 (d), 73.8 (d), 171.1 (s); IR (film) (cmK1) 2952, 2856,
1735; MS (FAB) m/z (relative intensity) 285 (MCH) (100),
225 (12), 220 (10). HRMS (FAB) calcd for C14H21O6 (MC
H): 285.1338, found: 285.1332.
(266 mg, 96% yield): [a]2D5K1.4 (c 1.4, CHCl3); H NMR
1
(CDCl3) d 0.03 (s, 3H), 0.05 (s, 3H), 0.90 (s, 9H), 1.28–1.42
(m, 2H), 1.65–1.98 (m, 6H), 2.44 (dd, JZ4.5, 15.9 Hz, 2H),
2.59–2.71 (m, 2H), 3.48 (ddddd, JZ2.0, 11.6, 11.6, 11.6,
11.6 Hz, 2H), 3.70 (s, 1H), 3.83–3.94 (m, 2H), 3.94–3.98
(m, 2H), 4.93 (s, 1H), 5.10 (d, JZ12.4 Hz, 1H), 5.12 (d, JZ
12.4 Hz, 2H), 7.28–7.36 (m, 5H); 13C NMR (CDCl3) dK4.8
(q), K4.5 (q), 18.1 (s), 20.4 (t), 25.9 (q), 27.8 (t), 30.9 (t),
37.3 (t), 66.4 (t), 67.2 (d), 67.4 (t), 68.1 (t), 68.6 (d), 74.7 (d),
76.3 (d), 128.1 (d), 128.5 (d), 135.8 (s), 170.8 (s), 171.2 (s);
IR (film) (cmK1) 2952, 2930, 2856, 1737; MS m/z (relative
intensity) 449 (MKBu-t)C (0.89), 307 (7), 233 (26), 187
(14), 91 (100). HRMS calcd for C23H33O7Si (MKBu-t)C:
449.1996, found: 449.1979.
4.1.14. Preparation of (2R,3R)-2-{(1E)-2-[benzyloxy-
carbonyl]vinyl}-tetrahydro-2H-pyran-3-yl 3-[(3S,2R)-3-
(tert-butyldimethylsilyloxy)-(tetrahydro-2H-pyran-2-
yl)]prop-2-(2E)-enoate (29). The same procedure used
above to obtain compound 27 was applied to the acid 23 on
a 350 mg (1.2 mmol) scale and alcohol 26 (320 mg,
1.2 mmol), yielding 29 (532 mg, 82% yield) as a colourless
oil: [a]2D5K9.8 (c 1.25, CHCl3); 1H NMR (CDCl3) d 0.03 (s,
3H), 0.01 (s, 3H), 0.84 (s, 9H), 1.30–1.44 (m, 2H), 1.65–
2.04 (m, 6H), 3.50 (m, 2H), 3.79 (s, 1H), 3.97–4.13 (m, 3H),
4.16 (s, 1H), 5.05 (s, 1H), 5.14 (s, 2H), 6.05 (d, JZ17.6 Hz,
1H), 6.11 (d, JZ17.6 Hz, 1H), 6.85 (m, 2H), 7.26–7.32 (m,
5H); 13C NMR (CDCl3) d 4.8 (q), 18.1 (s), 20.5 (t), 25.7 (q),
27.8 (t), 31.2 (t), 37.3 (t), 66.0 (t), 67.2 (t), 67.6 (d), 67.7 (t),
68.2 (d), 77.0 (d), 78.8 (d), 121.6 (d), 121.9 (d), 128.0 (d),
4.1.12. Preparation of (2R,3R)-2-[2-(benzyloxy)-2-
oxoethyl]tetrahydro-2H-pyran-3-yl [(2R,3R)-3-hydroxy-
tetrahydro-2H-pyran-2-yl]acetate (28). To a solution of
the benzyl ester 27 (266 mg, 0.5 mmol) in CH3CN (5.3 mL)
at 0 8C, was added HF (48%, 0.6 mL) and the reaction was

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R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
128.1 (d), 128.4 (d), 128.5 (d), 136.0 (s), 144.7 (d), 146.9
(d), 165.4 (s), 165.8 (s); Anal. Calcd for C29H42O7Si: C,
65.63; H, 7.98. Found: C, 65.65; H, 7.68.
(MCH)C (52), 307 (13), 263 (10). HRMS (FAB) calcd for
C23H33O9 (MCH)C: 453.2125, found: 453.2087.
4.1.18. Preparation of the macrodiolide (3) and macro-
tetraolide (34). A mixture of the alcohol 31 (580 mg,
1.28 mmol) and Pd(OH)2 (10 mg) in EtOAc (13 mL) was
placed under H2 atmosphere. The reaction mixture was
vigorously stirred until TLC showed complete conversion to
the hydroxyl acid 32. The mixture was filtered through a pad
of Celite. The solvent was removed under reduced pressure
and the residue was used without further purification.
4.1.15. Preparation of macrodiolide 2. To a solution of the
benzyl ester 29 (320 mg, 0.6 mmol) in CH3CN (5.4 mL) at
0 8C, was added HF (48%, 0.6 mL) and the reaction was
stirred for 3–4 h. Then, the mixture was diluted with Et2O
and washed with a saturated aqueous solution of NaHCO3.
The aqueous layer was extracted with Et2O and the
combined organic layers were dried (MgSO4), filtered and
concentrated. Silica gel column chromatography of the
residue gave the alcohol as an oil. Then, the same procedure
used above to obtain compound 1 was applied to the
alcohol, yielding macrodiolide 2 (90 mg, 48% overall yield)
For macrolactonization two methods were carried out.
1
as a colourless oil: [a]2D5C19.3 (c 0.3, CHCl3); H NMR
Method A. To a solution of the hydroxy acid 32 (27 mg,
0.07 mmol) in dry THF (6.13 mL, 0.012 M) at rt, were
added Et3N (20 mL, 0.15 mmol) and 2,4,6-trichlorobenzoyl
chloride (15 mL, 0.1 mmol). After 2 h, the mixture was
diluted with dry toluene (61 mL, 0.0012 M) and added
slowly over DMAP (90 mg, 0.7 mmol) in boiling toluene
(12 mL). The mixture was stirred at reflux for 1 h. The
solvent was evaporated and the residue purified by size
exclusion chromatography (Sephadex LH-20 and MeOH as
the mobile phase) to yield the macrodiolide (3) (5.1 mg,
20% yield) as an oil, and the macrotetraolide (34) (10.1 mg,
40% yield) as a white solid and oligomers (10 mg).
(CDCl3) d 1.39–1.44 (m, 2H), 1.69–1.79 (m, 2H), 1.85–2.10
(m, 6H) 2.15 (m, 2H), 2.47 (ddd, JZ3.4, 7.1, 18.0 Hz, 2H),
2.70 (ddd, JZ3.4, 11.1, 18.1 Hz, 2H), 3.53 (ddd, JZ2.1,
12.3, 12.3 Hz, 2H), 3.66 (ddd, JZ1.4, 3.4, 3.4 Hz, 2H), 3.99
(ddd, JZ2.3, 2.3, 11.4 Hz, 2H), 4.33 (s, 2H); 13C NMR
(CDCl3) d 19.9 (t), 25.6 (t), 26.1 (t), 28.7 (t), 68.1 (t), 69.7
(d), 75.9 (d), 171.8 (s); IR (film) (cmK1) 2928, 2853, 1730,
1246, 1024; MS (FAB) m/z (relative intensity) 313 (MC
H)C (19), 175 (6), 157 (100), 55 (56). HRMS (FAB) calcd
for C16H25O6 (MCH)C: 313.1651, found: 313.1661.
4.1.16. Preparation of (2R,3R)-2-{[(benzyloxycarbonyl)
methoxy]methyl}-tetrahydro-2H-pyran-3-yl 2-{[(2R,
3R)-3-(tert-butyldimethylsilyloxy)-tetrahydro-2H-
pyran-2-yl]methoxy}acetate (30). The same procedure
used above to obtain compound 27 was applied to the acid
18 on a 500 mg (1.6 mmol) scale and alcohol 19 (460 mg,
1.6 mmol), to afford the benzyl ester 30 (791 mg, 85%
yield): [a]2D5K19.6 (c 1.1, CHCl3); 1H NMR (CDCl3) d 0.03
(s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.25–1.43 (m, 2H), 1.60–
2.07 (m, 6H), 3.45–3.65 (m, 7H), 3.72 (dd, JZ1.4, 4.6 Hz,
1H), 3.79 (s, 1H), 3.94–4.05 (m, 2H), 4.10–4.17 (m, 4H),
5.00 (s, 1H), 5.16 (s, 2H), 7.31–7.38 (m, 5H); 13C NMR
(CDCl3) dK5.0 (q), K4.6 (q), 18.1 (s), 20.4 (t), 20.6 (t),
25.8 (q), 27.6 (t), 31.0 (t), 65.9 (d), 66.5 (t), 67.6 (t), 67.9 (t),
68.0 (d), 68.7 (t), 68.7 (t), 71.7 (t), 72.5 (t), 77.2 (d), 78.8 (d),
Method B. To a mixture of hydroxy acid 32 (50 mg,
0.14 mmol) and 2,20-dipyridyl disulfide (46 mg, 0.2 mmol)
in dry CH2Cl2 (2.75 mL, 0.05 M) at rt, was added
triphenylphosphine (55 mg, 0.2 mmol) in one portion. The
reaction mixture was stirred for 6 h prior to diluting with dry
CH2Cl2 (67 mL, 0.002 M) and subsequent addition of
K2CO3 (381 mg, 2.8 mmol), then the mixture was refluxed
for 6 days. The reaction was poured into saturated aqueous
NH4Cl and extracted with EtOAc. The organic layer was
dried over MgSO4, filtered and the solvent was removed
under vacuum. The residue was purified by size exclusion
chromatography (Sephadex LH-20 and MeOH as the mobile
phase) to yield the macrodiolide (3) (39 mg, 82% yield) and
the macrotetraolide (34) (6 mg, 13% yield). Macrodiolide
(3): [a]2D5K31.2 (c 0.33, CHCl3); H NMR (CDCl3) d 1.41
1
128.4 (d), 128.6 (d), 135.4 (s), 170.0 (s); IR (film) (cmK1
)
(d, JZ12.6 Hz, 2H), 1.68–1.77 (m, 2H), 1.85–1.97 (m, 2H),
2.10 (d, JZ14.2 Hz, 2H), 3.50 (ddd, JZ1.8, 1.8, 11.8 Hz,
2H), 3.62 (dd, JZ5.4, 5.4 Hz, 2H), 3.67–3.77 (m, 4H), 4.05
(d, JZ14.2 Hz, 4H), 4.16 (d, JZ14.3 Hz, 2H), 5.08 (s, 2H);
13C NMR (CDCl3) d 20.6 (t), 27.2 (t), 68.1 (t), 68.2 (d), 70.4
(t), 70.8 (t), 76.2 (d), 169.4 (s); IR (film) (cmK1): 2928,
2854, 1736, 1217, 1095; MS (FAB) m/z (relative intensity):
367 (MCNa)C (19), 135 (8), 81 (51), 69 (100). HRMS
(FAB) calcd for C16H24O8Na (MCNa)C: 367.1369, found:
367.1387. Macrotetraolide (34): mp 135–139 8C: [a]2D5K
42.7 (c 1.4, CHCl3); 1H NMR (CDCl3) d 1.40 (d, JZ
13.0 Hz, 4H), 1.57–1.92 (m, 8H), 2.06 (d, JZ13.4 Hz, 4H),
3.32–3.68 (m, 12H), 3.99 (m, 4H), 4.05 (d, JZ16.8 Hz, 4H),
4.21 (d, JZ16.8 Hz, 4H), 5.01 (s, 4H); 13C NMR (CDCl3) d
20.5 (t), 27.6 (t), 68.0 (d), 68.2 (t), 71.4 (t), 77.2 (d), 169.8
(s); IR (film) (cmK1): 2954, 2855, 2362, 1751, 1437, 1202,
1132, 1094; MS (FAB) m/z (relative intensity): 711 (MC
Na)C (8), 367 (5), 173 (16), 97 (100), 69 (17). HRMS
(FAB) calcd for C32H48O16Na (MCNa)C: 711.2840,
found: 711.2793.
2952, 2854, 1755, 1462, 1132, 1098; MS m/z (relative
intensity) 566 (M)C(0.12), 509 (MKBu-t)C (0.91), 387
(0.45), 263 (27), 187 (18), 91 (100). HRMS calcd for
C29H46O9Si (M)C: 566.2911, found: 566.2918.
4.1.17. Preparation of benzyl-2-{[(2R,3R)-3-(2-{[(2R,3R)-
3-hydroxy-tetrahydro-2H-pyran-2-yl]methoxy}acet-
oxy)-tetrahydro-2H-pyran-2-yl]methoxy}acetate (31).
The same procedure used above to obtain compound 28
was applied to the benzyl ester 30 on a 805 mg (1.4 mmol)
scale, yielding alcohol 31 (590 mg, 92% yield) as an oil:
1
[a]2D5K32.3 (c 1.2, CHCl3); H NMR (CDCl3) d 1.40 (dd,
JZ12.4, 12.4 Hz, 2H), 1.63–2.05 (m, 6H), 3.44–3.73 (m,
8H), 3.88 (s, 1H), 3.95–4.20 (m, 6H), 5.03 (s, 1H), 5.15 (s,
2H), 7.30–7.38 (m, 5H); 13C NMR (CDCl3) d 20.2 (t), 20.5
(t), 27.5 (t), 30.0 (t), 65.1 (d), 66.5 (t), 68.0 (t), 68.2 (d), 68.5
(t), 68.6 (t), 71.2 (t), 72.0 (t), 77.0 (d), 78.0 (d), 128.4 (d),
128.6 (d), 135.4 (s), 170.0 (s), 170.5 (s); IR (film) (cmK1
)
3489, 2949, 2854, 2361, 1751, 1437, 1201, 1130, 1093; MS
(FAB) m/z (relative intensity) 475 (MCNa)C (82), 453

R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
8189
4.1.19. Preparation of [(2R,3R)-3-(phenylmethoxy)-
tetrahydro-2H-pyran-2-yl]methan-1-ol (41). To a stirred
solution of diol 11 (2 g, 15.1 mmol) in dry CH2Cl2 (50 mL)
were sequentially added a catalytic amount of CSA
(175 mg, 0.8 mmol) and benzaldehydedimethyl acetal
(3.4 mL, 22.7 mmol) at rt. The reaction mixture was stirred
for 2 h, after which time TLC showed complete conversion
to the benzylidene derivative. Then Et3N was added until
pHz7, and the mixture was stirred for 5 min, evaporated
under reduced pressure and purified by silica gel flash-
chromatography.
atmosphere. The reaction mixture was vigorously stirred
until TLC showed complete conversion. The mixture was
filtered through a pad of Celite. The solvent was removed
under reduced pressure and the residue was purified by silica
gel flash-chromatography affording 43 (735 mg, 99%
1
overall yield) as an oil; H NMR (CDCl3) d 1.31 (m, 2H),
1.36–1.82 (m, 14H), 1.85–2.07 (m, 4H), 2.97 (d, JZ5.1 Hz,
1H), 3.09 (d, JZ5.1 Hz, 1H), 3.42–3.50 (m, 6H), 3.52–3.72
(m, 10H), 3.85 (m, 6H), 4.02 (m, 2H), 4.59 (s, 2H); 13C
NMR (CDCl3) d 19.4 (t), 20.0 (t), 20.1 (t), 25.3 (t), 30.2 (t),
30.5 (t), 62.2 (t), 62.3 (t), 65.9 (d), 66.1 (d), 66.3 (d), 66.4 (t),
68.6 (t), 68.7 (t), 70.8 (t), 70.9 (t), 72.4 (t), 72.6 (t), 77.9 (d),
78.0 (d), 98.9 (d), 99.0 (d); IR (film) (cmK1) 3464, 2942,
2869, 1441, 1126, 1035; Anal. Calcd for C13H24O5: C,
59.98; H, 9.29. Found: C, 59.89; H, 9.22.
To a stirred solution of the benzylidene derivative in dry
CH2Cl2 (150 mL) at 0 8C was added dropwise DIBAL-H
(76 mL, 1 M in hexane, 76 mmol). The reaction mixture
was stirred for 30 min and then quenched with water (3 mL)
and allowed to warm to rt. The mixture was stirred for
30 min, dried over MgSO4 and filtered through a pad of
Celite. The solvent was evaporated and the residue was
purified by silica gel flash-chromatography, yielding 41
(3.03 g, 90% overall yield) as an oil: [a]2D5K58.9 (c 2.1,
CHCl3); 1H NMR (CDCl3) d 1.35–1.49 (m, 2H), 1.96–2.15
(m, 2H), 2.34 (br s, 1H), 3.40–3.45 (m, 1H), 3.49 (s, 1H),
3.55 (dd, JZ4.2, 11.5 Hz, 1H), 3.84 (dd, JZ7.1, 11.5 Hz,
1H), 4.03 (m, 1H), 4.37 (d, JZ12.0 Hz, 1H), 4.65 (d, JZ
12.0 Hz, 1H), 7.30 (m, 5H); 13C NMR (CDCl3) d 20.7 (t),
25.8 (t), 63.5 (t), 68.0 (t), 70.6 (t), 71.9 (d), 79.5 (d), 127.7
4.1.22. Preparation of 2-{[(2R,3R)-3-(benzyloxy)-tetra-
hydro-2H-pyran-2-yl]methoxy}ethyl 4-methylbenzene-
sulfonate (44). To
a
stirred solution of the
tetrahydropyranyl ether 42 (1.2 g, 3.43 mmol) in dry
MeOH (34 mL) were added a few drops of HCl
(concentrated) at rt. The reaction mixture was stirred for
1 h, after which time TLC showed complete conversion.
Then Et3N was added until pHz7, and the mixture was
stirred for 5 min and evaporated under reduced pressure and
subjected to silica gel flash chromatography yielding the
alcohol (903 mg, 99% yield) as an oil: [a]2D5K19.8 (c 1.2,
CHCl3); 1H NMR (CDCl3) d 1.35–1.52 (m, 2H), 1.91–2.15
(m, 2H), 2.37 (s, 1H), 3.44–3.70 (m, 9H), 4.03 (m, 1H), 4.38
(d, JZ12.1 Hz, 1H), 4.65 (d, JZ12.1 Hz, 1H), 7.30 (m,
5H); 13C NMR (CDCl3) d 20.7 (t), 25.8 (t), 61.6 (t), 68.0 (t),
70.7 (t), 71.3 (d), 71.7 (t), 72.6 (t), 78.5 (d), 127.6 (d), 127.9
(d), 128.3 (d), 138.4 (s); IR (film) (cmK1) 3408, 2949, 2858,
1716, 1451, 1274, 1091; MS m/z (relative intensity): 267
(MCH)C(0.9), 205 (22), 105 (30), 91 (100).
(d), 127.9 (d), 128.4 (d), 138.2 (s), 170.1 (s); IR (film) (cmK1
)
3431, 2932, 2945, 2852, 1455, 1209, 1099; MS (FAB) m/z
(relative intensity): 245 (MCNa)C(16), 223 (MCH)C(43),
91 (100). HRMS (FAB) calcd for C13H18O3Na (MCNa)C:
245.1154, found: 245.1150.
4.1.20. Preparation of [2-(tetrahydro-2H-pyran-2-yloxy)
ethoxy][(2R,3R)-3-(phenylmethoxy)(tetrahydro-2H-
pyran-2-yl)]methane (42). To a solution of alcohol 41 (2 g,
9.0 mmol), THPOCH2CH2Cl (4.0 mL, 27.0 mmol), and
tetrabutylammonium hydrogen sulphate (138 mg,
0.4 mmol) was added dropwise aqueous 50% NaOH
(90.1 mmol), and the two-phase mixture was stirred
vigorously and maintained at 65 8C for 1 day under
nitrogen. The reaction mixture was taken up into CH2Cl2
and washed with water. The organic layer was dried
(MgSO4) and filtered through a layer of silica gel with
EtOAc as eluent. The solvent was evaporated and the
residue was purified by silica gel flash-chromatography,
A solution of alcohol (900 mg, 3.4 mmol) and p-toluene-
sulfonyl chloride (1.61 g, 8.5 mmol) in THF (6.8 mL) was
cooled with an ice-water bath, and a solution of KOH
(570 mg, 10.1 mmol) in water (0.6 mL) was added slowly
over 1 h. The ice-water bath was removed, and the system
was stirred for an additional 7 h. The resulting suspension
was poured into a mixture of CH2Cl2 and ice-water, and the
aqueous layer was extracted with CH2Cl2. The combined
organic solutions were washed three times with distilled
water, dried over MgSO4, and filtered and the solvent was
evaporated, after which the residue was purified by silica gel
flash-chromatography, yielding 44 (1.28 g, 90% yield) as an
1
yielding 42 (2.9 g, 92% overall yield) as an oil; H NMR
(CDCl3) d 1.25–1.90 (m, 16H), 1.92–2.08 (m, 4H), 3.49–
3.70 (m, 18H), 3.85 (m, 4H), 4.05 (m, 2H), 4.44 (d, JZ
12.1 Hz, 2H), 4.64 (m, 4H), 7.31 (m, 10H); 13C NMR
(CDCl3) d 19.4 (t), 19.5 (t), 25.4 (t), 26.0 (t), 26.0 (t), 30.5
(t), 62.1 (t), 62.2 (t), 66.5 (t), 66.6 (t), 68.0 (t), 70.5 (t), 70.7
(t), 70.7 (t), 70.9 (t), 70.9 (t), 71.4 (d), 71.5 (d), 71.5 (t), 78.4
(d), 78.5 (d), 98.8 (d), 98.9 (d), 127.5 (d), 127.9 (d), 128.2
(d), 138.6 (s); IR (film) (cmK1) 3437, 2944, 2869, 1717,
1273, 1124, 1035; MS m/z (relative intensity): 265 (MK
C5H9O)C (15), 159 (11), 105 (36), 91 (100); Anal. Calcd for
C20H30O5: C, 68.54; H, 8.63. Found: C, 68.11; H, 8.97.
1
oil: [a]2D5K12.8 (c 1.9, CHCl3); H NMR (CDCl3) d 1.33–
1.52 (m, 2H), 1.89–2.18 (m, 2H), 2.41 (s, 1H), 3.41–3.65
(m, 7H), 3.96 (m, 1H), 4.08–4.16 (m, 2H), 4.36 (d, JZ
12.1 Hz, 1H), 4.61 (d, JZ12.1 Hz, 1H), 7.30 (m, 5H), 7.76
(d, JZ8.3 Hz, 2H); 13C NMR (CDCl3) d 20.6 (t), 21.6 (q),
25.9 (t), 68.0 (t), 68.8 (t), 69.0 (t), 69.1 (t), 70.8 (t), 71.2 (d),
71.6 (t), 78.3 (d), 127.6 (d), 127.9 (d), 127.9 (d), 128.3 (d),
129.8 (d), 133.1 (s), 138.4 (s), 144.7 (s); IR (film) (cmK1
)
2949, 2860, 1716, 1356, 1176, 922; Anal. Calcd for
C22H28O6S: C, 62.84; H, 6.71; S, 7.63. Found: C, 62.86;
H, 7.19; S, 6.90.
4.1.21. Preparation of (2R,3R)-2-{[2-(tetrahydro-2H-
pyran-2-yloxy)ethoxy]methyl}-tetrahydro-2H-pyran-3-
ol (43). A mixture of the benzyl ether 42 (1 g, 2.9 mmol) and
Pd(OH)2 (20 mg) in EtOAc (28 mL) was placed under H2
4.1.23. Preparation of 2-{[(2R,3R)-3-(2-{[(2R,3R)-3-
(benzyloxy)-tetrahydro-2H-pyran-2-yl]methoxy}-
ethoxy)-tetrahydro-2H-pyran-2-yl]methoxy}ethanol

8190
R. Carrillo et al. / Tetrahedron 61 (2005) 8177–8191
(45). To a solution of alcohol 43 (416 mg, 1.6 mmol) and
tosylate 44 (672 mg, 1.6 mmol) in dry THF (16 mL) under
nitrogen was added NaH (77 mg, 1.92 mmol, 60% oil
dispersion) at 0 8C. The reaction mixture was stirred at
reflux for 16 h before dilution with Et2O. The mixture was
washed with aqueous saturated NH4Cl solution and then
dried, filtered, concentrated and purified by chromatography
on silica gel to yield the benzyl ether as an oil. Removal of
the THP-ether group using the acid conditions described
above afforded alcohol 45 (616 mg, 91% overall yield) as an
until TLC showed complete conversion (6 h). The mixture
was concentrated and purified by flash chromatography over
silica gel using 0.5:0.95 MeOH/CH2Cl2 to yield the crown
ether 6 (32 mg, 82% yield) as a white solid: mp 134–136 8C:
[a]2D5K69.9 (c 1.0, CHCl3); 1H NMR (CDCl3) d 1.32 (d, JZ
14.4 Hz, 2H), 1.41 (ddd, JZ1.9, 13.9, 13.9 Hz, 2H), 1.92
(m, 2H), 2.10 (d, JZ13.7 Hz, 2H), 3.31 (dd, JZ4.3, 8.0 Hz,
2H), 3.46 (m, 4H), 3.58 (m, 6H), 3.78 (m, 6H), 3.96 (dd, JZ
4.3, 11.0 Hz, 2H); 13C NMR (CDCl3) d 20.5 (t), 25.4 (t),
67.4 (t), 68.3 (t), 69.8 (t), 71.1 (d), 73.4 (t), 78.0 (d); IR
(film) (cmK1) 2928, 2854, 1447, 1138, 1097; MS (FAB) m/z
(relative intensity): 355 (MCK)C (5), 339 (MCNa)C (95),
317 (MCH)C (15), 307 (30), 154 (100), 136 (65). HRMS
(FAB) calcd for C16H28O6Na (MCNa)C: 339.1784, found:
339.1798.
1
oil: [a]2D5K28.5 (c 2.0, CHCl3); H NMR (CDCl3) d 1.24–
1.52 (m, 4H), 1.84–2.13 (m, 4H), 3.43–3.70 (m, 18H), 3.99
(m, 2H), 4.39 (d, JZ12.0 Hz, 1H), 4.63 (d, JZ12.0 Hz,
1H), 7.30 (m, 5H); 13C NMR (CDCl3) d 20.5 (t), 20.6 (t),
25.9 (t), 26.0 (t), 61.5 (t), 67.9 (t), 68.1 (t), 70.7 (t), 70.8 (t),
71.1 (t), 71.5 (d), 71.6 (t), 72.6 (t), 72.7 (d), 78.3 (d), 78.5
(d), 127.5 (d), 127.8 (d), 128.2 (d), 138.4 (s); IR (film) (cmK1
)
3439, 2945, 2860, 1716, 1452, 1274, 1093; MS m/z (relative
intensity): 423 (MKH)C (0.4), 159 (8), 105 (71), 91 (100).
HRMS calcd for C23H35O7 (MKH)C: 423.2383, found:
423.2364.
Acknowledgements
We thank the MCYT (PPQ2002-04361-C04-02) of Spain
and the Canary Islands Government for supporting this
research. R. C. thanks the Spanish MEC for an FPU
fellowship. T. M. thanks the Spanish MCYT-FSE for a
4.1.24. Preparation of 2-{[(2R,3R)-3-(2-{[(3S,2R)-3-
(phenylmethoxy)(tetrahydro-2H-pyran-2-yl)]methoxy}-
ethoxy)-tetrahydro-2H-pyran-2-yl]methoxy}ethyl 4-
methylbenzenesulfonate (46). The same procedure used
above to obtain compound 44 was applied to 45 on a 560 mg
(1.3 mmol) scale, yielding tosylate 46 (662 mg, 87% yield)
´
Ramon y Cajal contract.
Supplementary data
1
as an oil: [a]2D5K23.7 (c 1.3, CHCl3); H NMR (CDCl3) d
1.26–1.48 (m, 4H), 1.79–2.09 (m, 4H), 2.42 (s, 3H), 3.33–
3.69 (m, 16H), 3.91–4.02 (m, 2H), 4.12 (m, 2H), 4.40 (d,
JZ12.1 Hz, 1H), 4.64 (d, JZ12.1 Hz, 1H), 7.29 (m, 7H),
7.77 (d, JZ8.3 Hz, 2H); 13C NMR (CDCl3) d 20.6 (t), 20.7
(t), 21.6 (q), 26.0 (t), 26.1 (t), 67.9 (t), 68.0 (t), 68.3 (t), 68.8
(t), 69.2 (t), 70.8 (t), 71.6 (d), 71.7 (t), 72.8 (d), 78.3 (d), 78.6
(d), 127.5 (d), 127.8 (d), 127.9 (d), 128.2 (d), 129.8 (d),
133.1 (s), 138.6 (s), 144.7 (s); IR (film) (cmK1) 2946, 2863,
1716, 1356, 1176, 922; Anal. Calcd for C30H42O9S: C,
62.26; H, 7.32; S, 5.54. Found: C, 61.93; H, 7.74; S, 5.67.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.06.
034. X-ray data for compounds 1, 4, 6, 34 and 35.
Experimental details for the preparation of compounds 20,
21, trans-18, trans-19, trans-30, trans-31, 4, 35, 36, 37, 38,
1
39, 5, 40. H and 13C NMR spectra for compounds 1, 2, 3,
3$KC, 4, 5, 6, 7, 20, 21, 25, 34, 35. FAB spectra for
compounds 1, 2, 3, 3$KC, 4, 5, 6, 34 and 35; COSY, HSQC,
NOEs spectra for compounds 1, 3 and 3$KC.
4.1.25. Preparation of 2-[((2R,3R)-3-{2-[((2R,3R)-3-
hydroxy(tetrahydro-2H-pyran-2-yl))methoxy]ethoxy}-
tetrahydro-2H-pyran-2-yl)methoxy]ethyl 4-methyl-
benzenesulfonate (47). The same procedure used above
to obtain compound 43 was applied to 46 on a 600 mg
(1.04 mmol) scale, yielding alcohol 47 (502 mg, 99% yield)
References and notes
1. Agtarap, A.; Chamberlin, J. W.; Pinkerton, M.; Steinrauf, L. K.
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1
as an oil: [a]2D5K16.9 (c 1.6, CHCl3); H NMR (CDCl3) d
1.22–1.48 (m, 3H), 1.61 (m, 1H), 1.79–2.09 (m, 4H), 2.43
(s, 3H), 2.98 (br s, 1H), 3.37 (s, 1H), 3.43–3.70 (m, 14H),
3.85 (s, 1H), 3.96 (m, 2H), 4.13 (m, 2H), 7.32 (d, JZ8.3 Hz,
2H), 7.77 (d, JZ8.3 Hz, 2H); 13C NMR (CDCl3) d 20.0 (t),
20.5 (t), 21.5 (q), 26.0 (t), 30.2 (t), 66.1 (d), 67.9 (t), 68.3 (t),
68.6 (t), 68.8 (t), 69.1 (t), 71.1 (t), 71.4 (t), 72.7 (d), 72.8 (t),
78.0 (d), 78.1 (d), 127.9 (d), 129.7 (d), 133.0 (s), 144.7 (s);
IR (film) (cmK1) 3461, 2927, 2858, 1448, 1356, 1176, 1094;
MS m/z (relative intensity): 470 (MKH2O)C (6), 199 (27),
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56.54; H, 7.43; S, 6.56. Found: C, 56.34; H, 7.94; S, 6.42.
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´ ´
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of the silyl ether with HF in CH3CN.
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