Is potential coordination of alkali metal ions to stereodefined polyoxygenated cyclohexanes an adequate driving force for fostering the adoption of axial conformers?

Article abstract of DOI:10.1016/j.tet.2004.10.011

Inositol orthoesters have been developed as precursors to stereodefined hexakis polyoxygenated cyclohexanes. The objective of the study was to determine if all-trans systems could be coaxed by alkali metal ions into adopting the all-axial coordinative fea

Full text of DOI:10.1016/j.tet.2004.10.011

Tetrahedron 61 (2005) 231–240
Is potential coordination of alkali metal ions to stereodefined
polyoxygenated cyclohexanes an adequate driving force for
fostering the adoption of axial conformers?
a
b
b,
Leo A. Paquette,a, Peter R. Selvaraj, Karin M. Keller and Jennifer S. Brodbelt
*
*
aThe Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA
bDepartment of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, USA
Received 10 August 2004; revised 30 September 2004; accepted 4 October 2004
Abstract—Inositol orthoesters have been developed as precursors to stereodefined hexakis polyoxygenated cyclohexanes. The objective of
the study was to determine if all-trans systems could be coaxed by alkali metal ions into adopting the all-axial coordinative features. This
high level coordination cannot be matched by epimers whose only option is to experience monocomplexation. Only very low levels of
coordination were exhibited in solution by the ligands in question. Electrospray ionization mass spectrometry was also used to evaluate the
metal complexation properties of the inositol ligands based on competition experiments involving each ligand and one or more metals.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The concept of bifacial ligation relates to the capacity of a
single molecular entity to coordinate to a pair of metal ions
residing on opposite faces of the organic core in an ‘inside-
out’ sandwich relationship. The structural features intrinsic
to this phenomenon hold fundamental interest and could
potentially service a wide range of applications. However,
progress in this area has been slow, largely because of the
reluctance of candidate substrates to become involved in
appropriate modes of geometric alignment. For example,
the all-trans hexamethoxycyclohexane (1)1 and its hexa-
spirotetrahydrofuran homolog 22 are strikingly inert to
alkali metal ions. The overwhelming preference for outward
projection of the C–O bonds in 1 and 2 has been attributed3
to the operation of six stabilizing gauche interactions4 in the
all-O-equatorial conformer. Analogous vicinal stereo-
electronic contributions are absent in the axial counterparts.
Another deterrent is the energetic cost associated with
multiple projection of alkoxy groups axially on the same
face of a cyclohexane (ca. 2 kcal/mol for each 1,3-
interaction).3 The inability to gain access to the all-
O-axial arrangements dismisses any possibility of
coordination to metal ions.
One way to skirt this complication is to rigidly enforce the
proper conformational features as exemplified by 3.5 By
Keywords: Polyoxygenated cyclohexanes; Coordination; Alkali metal ions;
Electrospray mass spectrometry; Conformational biases.
taking advantage of an inositol orthoester platform, one
finds it possible ultimately to link both halves into a dimeric
arrangement.5a,6 Much like its monomeric building block,
* Corresponding authors. Tel.: C1 614 292 2520; fax: C1 614 292 1685
(L.A.P.); tel.: C1 512 471 0028; fax: C1 512 471 8696 (J.S.B.);
e-mail addresses: paquette.l@osu.edu; jbrodbelt@mail.cm.utexas.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.011

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L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
3 binds LiC ions very strongly. In addition, this homo-
ditopic ionophore exhibits a strong preference for 2:1
stoichiometry and a propensity for conversion to a rodlike
supramolecular ionic polymer. This reactivity conforms to
expectations for a bifacial ligand.
Despite these successes, the allure offered by multifunction-
alized cyclohexanes remains a siren call for more detailed
investigation. Several discoveries have been reported that
demonstrate the feasibility of projecting multiple oxyge-
nated centers in syn-axial fashion under the proper
circumstances. The first of these involves the natural
product muellitol (4), its three prenyl substituents being
adequate to predispose the peripheral hydroxyl groups for
adoption of the desired axial-rich conformational bias.7
Ring inversion in this manner can also be achieved by
introducing bulky silyl protecting groups. This pheno-
menon, known to occur already at the simple trans-1,2-
cyclohexanediol level (as 5/6),8 is presently recognized to
be operational as well in select scyllo-inositol derivatives
represented by 7 and 8.9 These effects are in contrast to the
state of affairs encountered in the corresponding alkyl ethers
and have, on the basis of detailed MM3 calculations, been
attributed to differences in repulsive and attractive steric
interactions.8b
The use of electrospray ionization mass spectrometry
(ESI-MS)11 for the study of host–guest complexation and
molecular recognition has expanded greatly over the past
decade,10,12–17 in large part because electrospray ionization
is sufficiently gentle that non-covalent complexes can be
transferred from the solution to the gas phase without
disruption of the binding interactions of the complexes.
Characterization of the binding properties and selectivities
of new ligands has traditionally been undertaken by well-
established NMR, potentiometric, spectrophotometric, and
microcalorimetric methods,18 but ESI-MS has gained
popularity due to its sensitivity, low sample consumption,
ability to give unambiguous information about the stoichio-
metries of complexes, and compatibility with a wide range
of solvents.12–17 Moreover, ESI provides a natural means to
bridge the solution to gas-phase transition, thus giving a
novel way to screen the binding properties of new ligands,
to evaluate solvent effects, and to probe self-assembly
strategies. One of our groups has been active in mapping the
strengths and limitations of ESI-MS for applications related
to molecular recognition,5c,19–32 and we report the examin-
ation of the binding selectivities and stoichiometries of
inositol derivatives in the present study.
There is thus some degree of variability in the consequences
of interactions between vicinal electron pairs or polar bonds
upon the relative stability of cyclohexyl conformations. In
the present exploratory study, we have sought to extend the
length of the side chains in a manner that could allow metal
ion complexation to materialize at sites more distal to the
interconnective ring. At issue is the capacity for binding to
two MC ions in the manner reflected in 10. The differing
stereochemistry of 11 disallows comparable bifacial
ligation, but could possibly serve as a comparative test
case for possible 1:1 complexation as in 12. Alternatively, a
number of factors such as solvation forces could conspire to
preclude the formation of entities such as 10 and 11. For this
reason, we have evaluated the capacity of polyethers of
generic formula 9 and 11 to bind to alkali metal ions both in
solution and in the gas phase, the latter by electrospray
ionization mass spectrometry.10
2. Results and discussion
2.1. Synthesis of the polyethers
In contemplating workable routes to the target systems,
pathways originating from the known inositol orthoesters 13
and 1933 came to be regarded as most feasible. Threefold
alkylation of the hydroxyl groups resident in 13 with
2-(benzyloxy)ethyl tosylate34 in DMF solution containing
sodium hydride provided 14 efficiently (Scheme 1). This
maneuver, in parallel with the like conversion of 15 to 16
had the purpose of proper chain elongation with positioning
of a readily removable benzyl protecting group at the end of
all six pendant b-alkoxy ethyl groups. Subsequent exhaus-
tive hydrogenolysis of 16 could then be accomplished in a

L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
233
Scheme 1.
manner that conveniently skirted the problem of bringing 17
into contact with water, a medium in which it is freely
soluble. Under the conditions adopted for the generation of
17, it proved necessary only to remove the palladium
catalyst by filtration and to evaporate the methanol in vacuo.
The formation of hexaacetate 18 was routinely achieved by
direct acylation of the solid so isolated.
Scheme 2.
A parallel thrust with triol epimer 19 proceeded with
essentially identical efficiency at each of the five steps
(Scheme 2). The capping of inositol by way of these
symmetrical intermediates was unmistakingly diagnosed at
each stage by 13C NMR spectroscopy. Evidence that
hydrolysis of the orthoester subunit in 14 and 20 was
accompanied by conformational ring inversion was derived
by comparison of 1H NMR spectra. The most notable
diagnostic is the appreciably deshielded nature of the
cyclohexyl methine protons in 20 (4.28–4.47 ppm) relative
to those in 21 (3.90–3.97 ppm).35 Similarly, the conversion
of 14 to 15 was accompanied by wholesale displacement
of all six methine protons to higher field (as 4.19–4.41 to
3.49–3.64 ppm, respectively).
The stage was now set to proceed to the hexamethoxy
derivatives 28 and 31. To take advantage of the ready
availability of triallyl orthoester 25,36 this heavily function-
alized system was subjected to sequential acid hydrolysis
and chain extension as before (Scheme 3). Once 26 became
available, recourse was made to ozonolysis to degrade the
allyl subunits. Direct reduction of the trialdehyde with
sodium borohydride gave rise to an intermediate that could
be processed without difficulty as in the conversion to
polyether 27. The route to 28 was completed uneventfully.
The convenience associated with distributing side chain
introduction into two distinctively separate operations holds
Scheme 3.
advantages. However, a shorter means for accomplishing a
comparable goal in a stereoisomeric series is available as
illustrated in Scheme 4. In this instance, the two
independent chain extensions were performed with
2-methoxyethanol tosylate.37 By this means, tribenzyl

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L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
dissecting changes in conformation brought on by ligation.
In the present study, 16 dissolved in CDCl3/CH3CN (1:1)
was titrated with 0.25 M equiv of lithium perchlorate until
an equimolar level had been reached. At each incremental
stage, the 1H and 13C spectra of the resulting solution were
recorded. Only very minor changes in carbon chemical
shifts were noted at the maximum level of lithium salt. The
same was true for the 1H spectra except for the six
equivalent protons on the cyclohexane ring which migrated
upfield from d 2.90 to 2.69. This singlet also underwent
some slight line broadening. These observations are viewed
as confirmatory of the absence of significant complexation
of 16 to LiC. The response of 22, a key member of the
cis,trans2 series, proved to be entirely comparable.
2.3. Electrospray ionization-mass spectrometry
measurements
Scheme 4.
ether 2938 could be transformed into 31 by way of only four
discrete steps. No yields reported herein are considered to be
optimized.
The metal complexation properties of each potential ligand
were assessed by analyzing solutions containing one host
and one metal salt in 19:1 chloroform/methanol. This
solvent mixture was employed to provide the closest
possible correlation with binding affinity/selectivity deter-
minations performed using conventional solution methods.
Using this solvent, solutions containing KCl but no added
NaCl produced signals consistent with complexation of
sodium rather than potassium. Sodium is ubiquitous on
glassware and in infusion tubing, and as a result sodium-
cationized species are often observed in electrospray
experiments even when no sodium is added. For compari-
son, 1:1 mixtures of ligand and metal salt were also
analyzed in methanol, and potassium complexes were
readily observed in this solvent.
2.2. Solution phase complexation studies
The solution-phase association constants (Ka) were deter-
mined for six of the polyethers defined above relative to
LiC, NaC, and KC picrates in a H2O–CHCl3 solvent
mixture according to Cram’s extraction protocol.39 The pair
of polyols 17 and 23 proved to be too insoluble in the
organic phase to allow measurements to be made. The data
compiled in Table 1 were conservatively determined with
relatively high concentrations of picrate salts so as to
normalize matters to the level of 1:1 complexes only. From
the outset, it became clear that the ability of the benzyl and
methyl ethers as well as the acetates to extract any of the
picrate salts was low. Compound 16 was defined as
exhibiting a very modest capability to complex lithium
ions. However, a Ka value of 2.38!10K4 represents a
chelating ability roughly three orders of magnitude lower
than that exhibited by 3. At least in solution therefore, little
tendency is seen for any of the alkali metal ions to position
itself comfortably in a binding pocket of the type
represented by 10 or 12.
In the presence of added NaCl or LiCl, the polyethers
produced abundant complexes from the 19:1 chloroform/
methanol solvent mixture. Electrospray spectra acquired for
17 and 23 (RZH) under these conditions are shown in
Figure 1. The most abundant ions in these spectra are the
metal-cationized ligands, (LCM)C where LZinositol
ligand and MZmetal, which suggests that the 1:1
stoichiometry is preferred for both ligand isomers.
Other stoichiometries were also observed at somewhat
lower abundance, including the interesting bimetallic
complexes of the general formula (LC2MCCl)C. In the
all-axial conformation, the ligands potentially present two
metal binding ‘cavities’, so the 1:2 ligand/metal stoichio-
metry was expected as a possibility. The observed retention
of ClK counterions in these species is rationalized because
the presence of the counterion reduces coulombic repulsion
within the complex and should thereby improve its gas-
phase stability. Ions of the general formulae (2LCM)C and
(2LC2MCCl)C are also observed in Figure 1A–D,
indicating that complexes containing two ligand moieties
exist for 17 and to a somewhat lesser extent for 23.
This conclusion is corroborated by NMR spectroscopy. The
latter technique is recognized to be a powerful tool for
Table 1. Association constants (Ka) determined by picrate extraction from
chloroform at 20 8C (!104)
Ka
½MCꢀaq C½PicKꢀaq C½hostꢀorg%½MC PicK hostꢀorg
Host
LiC
NaC
1.17
KC
1. All-trans series
16 (RZBn)
17 (RZH)
2.38
a
0.53
18 (RZAc)
31 (RZMe)
2. cis,trans2 series
22 (RZBn)
23 (RZH)
0.55
0.93
0.27
0.48
0.83
0.28
The other inositol ethers (RsH) produced a smaller number
of distinct complexes than 17 and 23 (spectra not shown).
The (LCM)C ions were still the major species formed in
the presence of both sodium and lithium, indicating that the
1:1 stoichiometry is again preferred. In many cases (LC
2MCCl)C ions were also major species. The (2LCM)C
1.65
a
0.18
0.23
24 (RZAc)
28 (RZMe)
0.96
0.61
1.40
0.56
0.10
0.06
a This host exhibits extremely limited solubility in CHCl3, thus precluding
data collection.

L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
235
Figure 1. Electrospray ionization mass spectra for equimolar solutions of (A) 17 and NaCl, (B) 17 and LiCl, (C) 23 and NaCl, and (D) 23 and LiCl in 19:1
chloroform/methanol.
ions were far less significant for these ligands (RsH), and
the (2LC2MCCl)C ions were not observed at all. This
suggests that steric hindrance prevents the formation of the
2:1 and 2:2 ligand/metal complexes in the analogs contain-
ing ether or ester groups at the end of each pendant arm.
bimetallic complexes in the more polar solvent. Further-
more, the (LC2MCCl)C ions were observed with greater
relative signal intensities for MZNa over MZLi, which
implies that bimetallic coordination is less favored for
smaller more charge-dense cations. Tight binding of a metal
ion in one cavity may distort the cyclohexane ring in such a
way as to disfavor coordination of a second metal.
The signal abundance ratios for (LC2MCCl)C to (LC
M)C complexes observed upon ESI-MS of both the 19:1
chloroform/methanol and 100% methanol solutions were
estimated for each ligand/metal combination, and the results
are given in Table 2. Inspection of these data (also echoed in
Fig. 1) shows that the bimetallic (LC2MCCl)C ions were
generally more abundant for the all-trans ligands than for
the cis,trans2 ligands. In fact, the enhancement ranges from
a factor of 2 to 6 for the all trans-ligands versus the
cis,trans2 ligands in chloroform/methanol (19:1) up to an
enhancement factor of 25 for 16 versus 22 in methanol. The
greater (LC2MCCl)C/(LCM)C ratios for the all-trans
ligands suggests that the three up–three down arrangement
of chelating arms enhances the formation of the bimetallic
complexes. The initial solvent environments also seem to
influence the formation of the bimetallic complexes. The
exaggeration of the (LC2MCCl)C/(LCM)C intensity
ratios for the methanol solutions relative to the chloroform/
methanol solutions suggests an increased stabilization of the
To further characterize the ligand–alkali metal interactions,
many of the complexes were individually isolated and
subjected to collisionally activated dissociation (CAD).
Typical results are shown in Figure 2 for the (LC2NaC
Cl)C and (2LC2NaCCl)C ions observed for 17. For the
(LC2NaCCl)C parent species, two major fragmentation
pathways are possible: loss of ClK to yield the doubly
charged (LC2Na)C2 ion, and loss of NaCl to yield the
singly charged (LCNa)C ion. The spectrum in Figure 2A
illustrates that the latter pathway is followed exclusively,
which lends support to notion that coulombic effects
destabilize (LC2M)C2 species. The same result was
obtained for all other (LC2MCCl)C ions probed by
CAD, regardless of the identity of either the ligand or the
metal. For the (2LC2NaCCl)C parent ions, several
fragmentation pathways might be expected to give obser-
vable products, including loss of ClK, loss of NaCl, loss of
L, and possibly loss of (LCNaCl)0. Of these, only loss of
one ligand was observed (Fig. 2B).
Table 2. Signal abundance ratios, (LC2MCCl)C/(LCM)C by ESI-MS
RZ
Ligand
SolventZ19:1
chloroform/methanol
SolventZmethanol
These CAD results shed some light on the structures of the
gas-phase complexes. Based on the exclusive loss of NaCl
from the bimetallic (LC2NaCCl)C complexes, these
structures are best rationalized as ones in which one metal
is strongly coordinated via electrostatic interactions with the
oxygen atoms on one face of the inositol plane, and NaCl is
more loosely bound as an ion pair on the other face of the
inositol plane. The (2LC2NaCCl)C ions are likely
sandwich complexes in which one NaC ion is bound
between two inositol ligands, and a NaCl ion pair is loosely
bound to the opposite faces of one of the inositol ligands.
MZNa
MZLi
MZK
MZNa
MZLi
Bn
Ac
H
16
22
1.0
0.2
0.5
0.25
0.8
0.03
0.25
0.01
0.03
0.01
18
24
0.3
0.1
0.1
0.03
1.2
0.1
0.2
0.03
0.15
0.03
17
23
0.6
0.1
0.3
0.1
0.4
0.3
0.25
0.05
0.05
0.1
Me
31
28
0.4
0.1
0.8
0.3
0.15
0.3
0.1
0.02
0.3
0.1

236
L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
Figure 2. Collisionally activated dissociation of (A) (17C2NaCCl)C, m/z 525 and (B) (2!17C2NaCCl)C, m/z 969. Asterisks mark the parent species.
Upon CAD, the exclusive loss of one of the inositol ligands
suggests that steric factors prevent strong binding of both
inositol ligands to the central metal ion.
entities are not conducive to orienting their side chains
axially in this medium. The ESI-MS results illustrate the
enhanced ability of the all trans ligands to form bimetallic
complexes of the type (LC2MCCl)C where LZinositol
ligand and MZmetal. Dissociation of the bimetallic
complexes suggests that one metal is coordinated to each
face of the inositol plane.
To assess the metal dependence of ligand binding, solutions
containing one inositol derivative and 1 equiv each of
lithium, sodium, and potassium chloride were analyzed by
ESI-MS. Results acquired for 17 and 23 are given in
Figure 3, and clearly show that (LCLi)C ions were the most
abundant species. Similar results were obtained for all other
analogs, indicating that the ligands in this series strongly
prefer lithium to sodium and potassium; neither the identity
of the substituents nor the arrangement of the chelating
groups on the cyclohexane core significantly altered the
metal selectivity.
3. Experimental
3.1. General
3.1.1. Compound 14. To triol 1333 (0.62 g, 3.2 mmol)
dissolved in dry DMF (25 mL) was added sodium hydride
(60%, 0.80 g, 19 mmol) followed by 2-(benzyloxy)ethyl
tosylate (5.97 g, 19.5 mmol) at 0 8C. The mixture was
stirred overnight with allowance for warming to rt, carefully
quenched with saturated NH4Cl solution, and extracted with
ether (4!75 mL). The combined organic layers were
washed with brine (4!100 mL), dried, and concentrated
to leave a residue that was purified by chromatography on
silica gel (elution with 20% ethyl acetate in hexanes) to
2.4. Overview
The ionophoric potential of polyethers of type 9 or 11 is
obviously dependent on recognition by the alkali metal ion
of the availability of ligating sites at the termini of the other
two chains residing in a 1,3-diequatorial relationship. For
the cation-binding properties of these potential hosts to
come into play in the manner defined in 10, numerous
solvent molecules require displacement so that a hold can be
gained on achieving proximity for the appropriate oxygen
atoms. The entropic and enthalpic costs of structural
rigidification will also need to be paid. The fact that alkali
metal ions, and particularly LiC, are not well accommo-
dated in an aqueous environment points up that these
afford 1.84 g (95%) of 14 as a colorless oil; IR (film, cmK1
)
1602, 1584, 1496; 1H NMR (300 MHz, CDCl3) d 7.27–7.24
(m, 6H), 7.17–7.12 (m, 6H), 7.08–7.03 (m, 3H), 5.65 (s,
1H), 4.41–4.29 (q, JZ2.9 Hz, 3H), 4.32 (s, 6H), 4.22–4.19
(q, JZ2.9 Hz, 3H), 3.45–3.41 (m, 6H), 3.38–3.34 (m, 6H);
13C NMR (75 MHz, CDCl3) d 139.1, 128.2, 127.5, 127.3,
Figure 3. Electrospray ionization mass spectra for equimolar solutions of (A) 17, LiCl, NaCl and KCl and (B) 23, LiCl, NaCl, and KCl in 19:1 chloroform/
methanol.

L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
237
103.4, 73.8, 72.9, 69.7, 68.9, 68.8; HRMS (electrospray) m/z
calcd for C34H40O9NaC 615.2564, found 615.2510.
4.7 Hz, 12H), 3.52–3.48 (t, JZ4.9 Hz, 12H), 3.32 (s, 18H),
3.12 (s, 6H); 13C NMR (75 MHz, CDCl3) d 83.1, 72.6, 72.2,
58.7; HRMS (electrospray) m/z calcd for C30H48O18NaC
719.2733, found 719.2738.
3.1.2. Compound 15. A solution of 14 (2.2 g, 3.7 mmol)
and p-toluenesulfonic acid (0.04 g, 0.19 mmol) in methanol
(75 mL) was refluxed for 4 h. The solvent was reduced to
about 10 mL and the reaction mixture was quenched with
saturated sodium carbonate solution (50 mL) and water
(75 mL), and extracted with ether (3!100 mL). The
organic extracts were combined, dried, and evaporated.
The residue was purified by chromatography on silica gel
(elution with 40% hexanes in ethyl acetate) to afford 15 as a
colorless oil (2.0 g, 92%); IR (film, cmK1) 3428, 1496,
3.1.6. Compound 20. A solution of 19 (0.5 g, 2.6 mmol) in
DMF (20 mL) was added dropwise to a stirred suspension of
sodium hydride (60%, 0.4 g, 10 mmol) in DMF (30 mL) at
0 8C. the reaction mixture was stirred for 20 min prior to
dropwise addition of solution of benzyloxyethyl tosylate
(3.22 g, 10.5 mmol) in DMF (25 mL), stirred overnight with
warming to rt, and quenched by careful addition of water
(100 mL) followed by three extractions with diethyl ether
(150 mL). The combined organic extracts were extracted
with brine, dried, and evaporated. The residue was purified
by flash chromatography on silica gel (5:1, hexanes/ethyl
acetate) to afford 20 (1.40 g, 90%) as a colorless oil; IR
(film, cmK1) 1498, 1453, 1166; 1H NMR (300 MHz,
CDCl3) d 7.36–7.24 (m, 15H), 5.53 (d, JZ1.2 Hz, 1H),
4.57 (s, 2H), 4.49 (s, H), 4.47–4.46 (m, 1H), 4.39–4.37 (m,
2H), 4.31–4.28 (t, JZ3.5 Hz, 2H), 3.94–3.93 (d, JZ1.5 Hz,
1H), 3.80–3.62 (m, 8H), 3.60–352 (t, JZ4.7 Hz, 4H); 13C
NMR (75 MHz, CDCl3) d 138.2, 138.1, 128.9, 128.2, 127.7,
127.6, 127.5, 103.9, 74.8, 73.2, 73.1, 70.4, 69.6, 69.4, 69.1,
69.0, 68.7, 67.9; HRMS (electrospray) m/z calcd for
C34H40O9NaC 615.2565, found 615.2551.
1
1453; H NMR (300 MHz, CDCl3) d 7.34–7.26 (m, 15H),
4.58 (s, 6H), 4.00–3.98 (t, JZ4.7 Hz, 6H), 3.64–3.61 (t, JZ
4.7 Hz, 6H), 3.64–3.61 (t, JZ9.4 Hz, 6H), 3.55–3.49 (t, JZ
9.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 137.6, 128.4,
127.9, 127.8, 83.9, 73.7, 73.1, 72.2, 69.6; HRMS (electro-
spray) m/z calcd for C33H42O9NaC 605.2721, found
605.2712.
3.1.3. Compound 16. Triol 15 (2.52 g, 4.32 mmol) was
dissolved in dry DMF (100 mL), treated with sodium
hydride (0.86 g, 22 mmol), and cooled to 0 8C. 2-(Benzyl-
oxy)ethyl tosylate (5.30 g, 17.3 mmol) was introduced and
the mixture was stirred overnight, quenched with methanol
(10 mL), and poured into an ice–water mixture prior to
extraction with ether (3!100 mL). The combined organic
extracts were dried and freed of solvent to afford a residue
that was purified by chromatography on silica gel (elution
with 33% ethyl acetate in hexanes) to afford 3.84 g (90%) of
16 as a colorless oil that crystallized in the cold, mp
77–79 8C; (film, cmK1) 1497, 1454, 1357; 1H NMR
(300 MHz, CDCl3) d 7.36–7.26 (m, 30H), 4.54 (s, 12H),
4.06–4.03 (m, 12H), 3.62–3.58 (m, 12H), 3.28 (s, 6H); 13C
NMR (75 MHz, CDCl3) d 138.5, 128.3, 127.7, 127.5, 83.1,
73.0, 72.9, 70.0; HRMS (electrospray) m/z calcd for
C60H72O12NaC 1007.4916, found 1007.4913.
3.1.7. Compound 21. A solution of 20 (2.90, 4.89 mmol)
and p-toluenesulfonic acid (7.6 mg, 0.04 mmol) in 100 mL
of methanol was refluxed for 4 h and evaporated to leave a
residue that was purified by chromatography on silica gel
(elution with 1:1 ethyl acetate in hexanes). There was
isolated 2.56 g (90%) of 21 as a colorless oil; IR (film, cmK1
)
3446, 1276, 1114; 1H NMR (300 MHz, CDCl3) d 7.34–7.25
(m, 15H), 4.57–4.56 (m, 6H), 3.97–3.90 (m, 6H), 3.86 (s, 1H),
3.63–3.58 (m, 6H), 3.47–3.42 (m, 5H), 3.13 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 137.41, 137.35, 128.18, 128.16, 127.6,
127.5, 83.4, 81.0, 74.2, 72.9, 72.6, 72.1, 69.5, 69.4; HRMS
(electrospray) m/z calcd for C33H42O9NaC 605.2721, found
605.2669.
3.1.4. Compound 17. To a solution of 16 (0.60 g,
0.61 mmol) in methanol (10 mL) was added palladium on
charcoal (10%, 20 mg) and hydrogen was purged through
the system followed by stirring under an atmosphere of
hydrogen for 6 h. The mixture was filtered through a Celite
plug and the solvent was removed in vacuo to afford polyol
17 in almost quantitative yield (0.27 g, 99%) as a white
solid, mp 260 8C dec. Further purification was not required;
3.1.8. Compound 22. To triol 21 (2.56 g, 4.40 mmol),
dissolved in dry DMF (100 mL) was added sodium hydride
(60%, 1.2 g, 30 mmol) followed by 2-(benzyloxy)ethyl
tosylate (6.74 g, 22 mmol) at 0 8C. The mixture was stirred
overnight, allowed to warm up gradually to rt, quenched
with saturated NH4Cl solution, and extracted with ether
(4!100 mL). The combined organic layers were washed
with brine (4!100 mL), dried, and concentrated to leave a
residue that was purified by chromatography on silica gel
(elution with 50% ethyl acetate in hexanes) to afford 3.61 g
(84%) of 22 as a colorless oil; IR (film, cmK1) 1602, 1496,
1
IR (film, cmK1) 3373, 1458, 1355; H NMR (300 MHz,
CDCl3) d 4.57–4.54 (t, JZ5.4 Hz, 6H), 3.70 (t, JZ5.1 Hz,
12H), 3.54–3.45 (q, JZ5.1 Hz, 12H), 3.05 (s, 6H); 13C
NMR (75 MHz, CDCl3) d 82.2, 74.5, 60.8; HRMS
(electrospray) m/z calcd for C18H36O12NaC 467.2099,
found 467.2098.
1
1453; H NMR (300 MHz, CDCl3) d 7.40–7.26 (m, 30H),
4.60 (s, 2H), 4.54–4.53 (10H), 4.05–3.97 (m, 9H), 3.81–3.58
(m, 19H), 3.24–3.16 (m, 3H); 13C NMR (75 MHz, CDCl3) d
138.8, 138.5, 138.4, 128.3, 128.2, 127.6, 127.5, 127.4,
127.3, 99.7, 83.9, 82.0, 81.3, 76.4, 73.1, 72.9, 72.8, 72.85,
72.75, 72.5, 72.3, 70.4, 70.1, 70.0, 69.91, 69.88; HRMS
(electrospray) m/z calcd for C69H72O12NaC 1007.4916,
found 1007.4834.
3.1.5. Hexaacetate 18. A suspension of 17 (0.88 g,
2.0 mmol) in acetonitrile (25 mL) cooled to 0 8C was
treated with triethylamine (1.8 mL, 13 mmol) followed by
acetic anhydride (1.15 mL, 12 mmol). The mixture was
allowed to warm gradually to rt, freed of acetonitrile, and
purified by flash chromatography on silica gel (15%
methanol in ethyl acetate) to afford 18 (1.26 g, 92%) as a
white solid, mp 157–159 8C; IR (film, cmK1) 1738, 1464,
1384; 1H NMR (300 MHz, CDCl3) d 3.90–3.87 (t, JZ
3.1.9. Polyol 23. To a solution of 22 (3.61 g, 3.66 mmol) in
methanol (100 mL) was added palladium on charcoal (10%,

238
L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
150 mg) and hydrogen was purged through the system
followed by stirring under 1 atm for 6 h. The mixture was
filtered through a Celite plug, solvent removed in vacuo, and
the residue was purified by recrystallization (50% methanol
in ethylacetate) to afford 1.57 g (96%) of 23 as a white solid,
dried, and freed of solvent to afford a residue that was
dissolved in dry DMF (100 mL). The resulting solution was
treated first with sodium hydride (1.25 g, 31.3 mmol) at
K10 8C and then slowly with dimethyl sulfate (3 mL,
31.3 mmol). After overnight stirring, the reaction mixture
was quenched with methanol (10 mL), poured into water
(200 mL), and extracted with ether (3!100 mL). The
organic extracts were combined, dried, and freed of solvent
to afford crude product that was chromatographed on silica
gel (elution with 60% ethyl acetate in hexanes) to afford 27
(4.15 g, 70% over three steps) as a colorless oil; IR (film,
1
mp 104–106 8C; IR (film, cmK1) 3386, 1461, 1361; H
NMR (300 MHz, CDCl3) d 4.60–4.52 (m, 5H), 4.34–4.30 (t,
JZ5.6 Hz, 1H), 3.93 (s, 1H), 3.70–3.31 (m, 26H), 3.17–3.13
(m, 2H), 3.02–2.96 (t, JZ9.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 94.8, 83.0, 81.2, 80.1, 75.2, 74.5, 74.3, 73.9, 71.8,
60.84, 60.78, 60.7, 60.6; HRMS (electrospray) m/z calcd for
C18H36O12NaC 467.2099, found 467.2098.
1
cmK1) 1453, 1354, 1094; H NMR (300 MHz, CDCl3) d
7.33–7.24 (m, 15H), 4.56 (s, 2H), 4.53 (s, 4H), 4.00–3.97
(m, 2H), 3.93–3.84 (m, 7H), 3.76–3.71 (m, 4H), 3.68–3.59
(m, 8H), 3.53–3.52 (m, 6H), 3.32 (s, 3H), 3.29 (s, 6H), 3.16–
3.08 (m, 3H); 13C NMR (75 MHz, CDCl3) d 138.6, 138.4,
128.3, 128.2, 127.6, 127.53, 127.50, 127.4, 83.4, 82.1, 81.3,
76.2, 73.1, 72.9, 72.7, 72.4, 72.2, 72.0, 70.4, 70.2, 69.9,
58.8, 58.7; HRMS (electrospray) m/z calcd for
C42H60O12NaC 779.3977, found 779.3958.
3.1.10. Hexaacetate 24. A suspension of 23 (100 mg,
0.22 mmol) in dry acetonitrile (50 mL) was treated with
triethylamine (0.4 mL, 2.70 mmol) and DMAP (2.7 mg,
0.02 mmol), and cooled to 0 8C. Following the addition of
acetic anhydride (0.3 mL, 2.70 mmol), the reaction mixture
was stirred for 2 h, quenched with saturated bicarbonate
solution (30 mL), and extracted with CH2Cl2 (3!50 mL).
The combined organic layers were dried and freed of
solvent. The residue was chromatographed on silica gel
(elution with 75% ethyl acetate in hexanes) to afford 142 mg
3.1.13. Hexamethoxy derivative 28. Compound 27 (2.0 g,
2.4 mmol) was dissolved in ethyl acetate (75 mL) followed
by palladium on charcoal (10%, 200 mg). The mixture was
purged with hydrogen and stirred in this atmosphere for 3 h.
The catalyst was removed by filtration through a cotton plug
and the filtrate was evaporated. The residue obtained was
dissolved in THF, treated with sodium hydride (0.37 g,
9.25 mmol), and cooled to K20 8C prior to the addition of
dimethyl sulfate (1.0 mL, 10.57 mmol). This mixture was
stirred for 4 h, allowed to warm gradually, and quenched
with methanol (5 mL). Solvent was removed in vacuo and
the residue was purified by chromatography on silica gel
(elution with 5% methanol in ethyl acetate) to afford 28 as a
colorless oil (1.2 g, 82%); IR (film, cmK1) 1454, 1356,
(91%) of 24 as a white solid, mp 57–59 8C; (film, cmK1
)
1739, 1440, 1382; 1H NMR (300 MHz, CDCl3) d 4.11–4.01
(m, 12H), 3.85–3.63 (m, 12H), 3.50–3.43 (t, JZ9.4 Hz,
2H), 2.98–2.90 (m, 3H), 1.92 (s, 18H); 13C NMR (75 MHz,
CDCl3) d 170.63, 170.58, 83.2, 81.3, 80.7, 76.2, 71.1, 70.9,
70.7, 69.8, 63.9, 63.8, 63.53, 63.47, 20.7, 20.6; HRMS
(electrospray) m/z calcd for C30H48O17NaC 719.2733,
found 719.2738.
3.1.11. Compound 26. A solution of 25 (2.64 g, 8.51 mmol)
and p-toluenesulfonic acid (80 mg, 0.05 mmol) in methanol
(150 mL) was refluxed for 4 h. The solvent was removed
and the residue was dissolved in dry DMF (150 mL), treated
with sodium hydride (1.36 g, 34.0 mmol), and cooled to
0 8C. 2-(Benzyloxy)ethyl tosylate (9.12 g, 29.77 mmol) was
introduced and the reaction mixture was stirred overnight,
quenched with methanol (10 mL), poured into an ice–water
mixture, and extracted with ether (3!100 mL). The
combined organic extracts were dried and evaporated. The
residue was purified by chromatography on silica gel
(elution with 25% ethyl acetate in hexanes) to afford
5.50 g (92% over two steps) of 26 as a colorless oil; IR (film,
1
1267; H NMR (300 MHz, CDCl3) d 3.89–3.78 (m, 10H),
3.71–3.63 (m, 3H), 3.59–3.53 (t, JZ9.6 Hz, 1H), 3.50–3.43
(m, 12H), 3.30–3.29 (m, 19H), 3.08–3.01 (m, 3H); 13C
NMR (75 MHz, CDCl3) d 83.9, 81.9, 81.3, 76.0, 72.5, 72.3,
72.2, 72.1, 71.9, 70.2, 58.8, 58.7, 58.7, 58.6; HRMS
(electrospray) m/z calcd for C24H48O12NaC 551.3038,
found 551.3037.
3.1.14. Compound 29. Triol 1333 (4.0 g, 21.0 mmol)
dissolved in anhydrous DMF (100 mL) at 0 8C was treated
with sodium hydride (60%, 3.0 g, 75.0 mmol), followed by
benzyl bromide (8.35 mL, 70 mmol) after 30 min. The
mixture was stirred overnight, quenched with saturated
NH4Cl solution (200 mL), and extracted with CH2Cl2
(3!100 mL). The combined organic layers were dried
and concentrated to leave a residue that was purified by
chromatography on silica gel (elution with 5% ethyl acetate
in hexanes) to afford 8.55 g (88%) of 29 as a white solid, mp
1
cmK1) 1496, 1454, 1354; H NMR (300 MHz, CDCl3) d
7.37–7.26 (m, 15H), 6.04–5.89 (m, 3H), 5.30–5.07 (m, 6H),
4.59–4.57 (m, 6H), 4.34–4.34 (m, 5H), 4.00–3.97 (m, 3H),
3.78–3.58 (m, 13H), 3.17–3.11 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 138.5, 138.4, 136.0, 135.8, 128.5,
128.4, 128.3, 127.8, 127.6, 127.5, 116.4, 116.2, 84.3, 81.7,
81.2, 74.4, 74.2, 73.3, 73.2, 73.0, 72.9, 71.4, 70.5; HRMS
(electrospray) m/z calcd for C42H54O9NaC 725.3660, found
725.3684.
1
117–119 8C; IR (film, cmK1) 1497, 1453, 1167; H NMR
(300 MHz, CDCl3) d 7.28–7.17 (m, 5H), 5.55 (s, 1H), 4.66
(s, 6H), 4.60–4.57 (dd, JZ4.2, 3.0 Hz, 3H), 4.38–4.36 (dd,
JZ4.2, 3.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 137.8,
128.1, 127.7, 127.4, 103.1, 72.5, 71.2, 68.6; HRMS
(electrospray) m/z calcd for C28H28O6NaC 438.1778,
found 483.1764.
3.1.12. Compound 27. Ozone was bubbled through a
solution of 26 (5.50 g, 7.83 mmol) in methanol/dichloro-
methane mixture (9:1, 100 mL) at K78 8C followed by the
addition of sodium borohydride (1.48 g, 38.1 mmol) after
reaction was complete. The mixture was stirred for 3 h and
allowed to gradually warm to rt prior to quenching by slow
addition of saturated NH4Cl solution and extraction with
ether (3!100 mL). The organic extracts were combined,
3.1.15. Compound 30. A solution of 29 (2.4 g, 5.2 mmol)
and p-toluenesulfonic acid (0.05 g, 0.26 mmol) in methanol

L. A. Paquette et al. / Tetrahedron 61 (2005) 231–240
239
was refluxed for 3 h, cooled, and freed of solvent. The crude
Supplementary data
residue was dissolved in dry DMF (75 mL) followed by the
addition of sodium hydride (0.73 g, 18.24 mmol) and
cooling to 0 8C. 2-Methoxyethanol tosylate (4.20 g,
18.2 mmol) was introduced and the reaction mixture was
allowed to warm gradually during overnight stirring,
quenched with methanol (10 mL) and water (100 mL),
and extracted with ether (3!100 mL). The organic extracts
were combined, dried, and evaporated to afford a residue
that was purified on silica gel (elution with 25% ethyl
acetate in hexanes) to afford 30 (2.95 g, 90%) as a white
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tet.2004.10.011
References and notes
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1
solid, mp 95–97 8C; IR (film, cmK1) 1454, 1356, 1198; H
NMR (300 MHz, CDCl3) d 7.46–7.26 (m, 15H), 4.90 (s,
6H), 3.99–3.95 (m, 6H), 3.55–3.48 (m, 9H), 3.35 (s, 9H),
3.30–3.24 (t, JZ9.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
138.9, 128.4, 128.2, 127.6, 83.4, 82.5, 75.8, 73.0, 72.3, 59.0;
HRMS (electrospray) m/z calcd for C36H48O9NaC
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1487, 1462, 1358; 1H NMR (300 MHz, CDCl3) d 3.90–3.87
(m, 12H), 3.52–3.48 (m, 12H), 3.32 (s, 18H), 3.12 (s, 6H);
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