Isolation of a bis-iodurated tetra-THF as a trace product from the oxidation of squalene with RuO4 and its double ring expansion to a novel bis-THF-bis-THP compound

Article abstract of DOI:10.3390/molecules16075362

A novel bis-iodurated polyether compound, based on an unprecedented tetra- THF backbone, has been isolated as a trace by-product of the oxidation of squalene with the catalytic system RuO₂ (cat.)/NaIO₄. The double erythro configuration of the central portion of the molecule furnishes the first indirect support of the previously postulated pathway operating in the oxidative pentacyclization of the isoprenoid substrate. A bidirectional double oxidative bis-cyclization is invoked to explain the formation of this compound. The isolated substance was successfully subjected to a double rearrangementring expansion to give a novel bis-THF-bis-THP compound.

Full text of DOI:10.3390/molecules16075362

Molecules 2011, 16, 5362-5373; doi:10.3390/molecules16075362
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Isolation of a Bis-Iodurated Tetra-THF as a Trace Product from
the Oxidation of Squalene with RuO4 and Its Double Ring
Expansion to a Novel bis-THF-bis-THP Compound
Vincenzo Piccialli 1,*, Sabrina Zaccaria 1, Roberto Centore 2, Angela Tuzi 2, Nicola Borbone 3
and Giorgia Oliviero 3
1
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli "Federico II",
Via Cynthia 4, 80126, Napoli, Italy; E-Mail: sabrina.zaccaria@unina.it (S.Z.)
2
Dipartimento di Chimica ‘‘Paolo Corradini’’, Università degli Studi di Napoli ‘‘Federico II’’, Via
Cinthia 4, 80126, Napoli, Italy; E-Mails: roberto.centore@unina.it (R.C.);
angela.tuzi@unina.it (A.T.)
3
Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli "Federico II",
Via D. Montesano 49, 80131, Napoli, Italy; E-Mails: nicola.borbone@unina.it (N.B.);
golivier@unina.it (G.O.)
* Author to whom correspondence should be addressed; E-Mail: vinpicci@unina.it.;
Tel.: +39-081-674111; Fax: +39-081-674393.
Received: 2 June 2011; in revised form: 20 June 2011 / Accepted: 21 June 2011 /
Published: 27 June 2011
Abstract: A novel bis-iodurated polyether compound, based on an unprecedented tetra-
THF backbone, has been isolated as a trace by-product of the oxidation of squalene with
the catalytic system RuO2(cat.)/NaIO4. The double erythro configuration of the central
portion of the molecule furnishes the first indirect support of the previously postulated
pathway operating in the oxidative pentacyclization of the isoprenoid substrate. A
bidirectional double oxidative bis-cyclization is invoked to explain the formation of this
compound. The isolated substance was successfully subjected to a double rearrangement-
ring expansion to give a novel bis-THF-bis-THP compound.
Keywords: ruthenium tetroxide; squalene; poly-THF; tetrahydrofuran; tetrahydropyran;
rearrangement-ring expansion

Molecules 2011, 16
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1. Introduction
Some years ago we discovered a novel cascade process catalysed by RuO4 generated in situ by the
action of NaIO4 on RuO2, the pre-catalytic species employed to generate RuO4 [1]. This is a unique
process by which a poly-THF backbone, made up of adjacently linked THF rings, can be built-up in a
single step and in a stereoselective manner starting from polyenes characterized by a repetitive
1,5-diene structural motif [2-8]. In particular, oxidation of squalene gives rise to penta-THF compound
1 (Scheme 1) containing ten stereogenic centres. Previous studies carried out in our group had suggested
that steric and chelation control factors concur to determine the stereochemical outcome of the process [6].
Scheme 1. Stereoselective synthesis of a pentacyclic poly-THF (1) by RuO4-catalysed
oxidative polycyclization of squalene.
.
RuO2 2H2O (cat.)
24
HO
NaIO4 (8 equiv.)
1
O
O
O
O
28
O
29
Oxidative
pentacyclization
OH
H
H
H
H
H
H
25
26
27
Squalene
1
In a more recent investigation, the use of different cyclization conditions led to a different
stereochemistry of the process [9]. In particular, four new C30 isomeric heptacyclic polyether
substances (compounds 2-5, Scheme 2) were obtained through a unique seven-step cascade process
featuring a pentacyclization of squalene followed by a double oxidative spiroketalization at the two
bis-THF termini of the first-formed penta-THF intermediates. Careful HPLC isolation of latter
substances for X-ray studies [9] allowed also the isolation of tetra-THF 6 (Scheme 2), a very minor
side-product of the process, possessing a CS-symmetric structure embodying two terminal cis-threo-
trans bis-THF moieties connected by a central bis-iodurated tetracarbonious segment. The
determination of the stereostructure of compound 6, the mechanistic implication of its isolation as well
as its double rearrangement-ring expansion to a new bis-THP polyether compound, are discussed in the
present paper.
Scheme 2. Synthesis of polycyclic polyethers by one-step RuO4-catalysed oxidative
polycyclization/oxidative spiroketalization of squalene.
Spiroketalization
Spiroketalization
.
RuO2 2H2O (cat.)
OH
18
HO
7
A
B
D
E
NaIO4 (8 equiv.)
C
30
24
1
O
26
O
O
O
28
O
H
H
H
H
H
H
Oxidative
pentacyclization
25
27
29
Squalene
All-threo, penta-THF
intermediates
New conditions
(ref. 2)
Double oxidative
spiroketalization
cis
cis
H
E
O
threo
erythro
erythro threo
29
26
H
A
O
1
3
30
10
15
O
6
B
+
D
O
C
O
1
14
11 I
OH
O
O
O
O
O
O
7
18
I
H
H
H
H
HO
H
H
25
24
27
28
cis/trans
cis/trans
6 (minor product)
cis/trans
Four isomers
2:cis/cis/cis/cis/cis; 3:cis/cis/trans/cis/cis
4:cis/trans/cis/trans/cis; 5:cis/cis/cis/trans/cis

Molecules 2011, 16
5364
2. Results and Discussion
2.1. Chemistry
The structure of compound 6 was determined by X-ray diffraction analysis carried out on a single
crystal of the substance obtained by slow evaporation of a chloroform solution. The most interesting,
and unusual feature of this compound is the double erythro configuration around the C10/C11 and
C14/C15 bonds. In fact, previous studies from our group had demonstrated that the oxidation of both
linear and isoprenoid polyenes constantly furnishes poly-THF compounds possessing threo inter-THF
relationships. This is consistent with the syn addition (a [3+2] cycloaddition) of a O=Ru-O portion
across each involved C-C double bond, along the all-trans polyene chain (Scheme 3), that also agrees
with mechanistic proposals for related oxidative mono-cyclization of 1,5-dienes catalysed by RuO4
-
[10-15] and related oxo-species OsO4 [16-18] and MnO4 [19-27], as well as rhenium (VII)-mediated
oxidative polycyclization of hydroxypolyenes [28-31].
Scheme 3. Ru-catalysed cascade sequence leading to penta-THF 1.
threo
[3+2]
cycloaddition
6
2
6
O
cis
Ru
2
6
10
O
O
H
(First cyclization
cis-selective)
O
O
Ru
Squalene
O
O
O
Ru
O
O
O
O
Ruthenium (VI)
diester
O
O
NaIO4
Ru oxidation
Further
cyclization
steps
threo
threo
10
[3+2] cycloaddition
2
10
O
O
O
O
O
H
(Second, cis-selective,
cyclization then Ru
oxidation)
O
OH
H
H
H
H
H
H
HO
O
O
HO
ORuO
H
H
H
3
Ru
1 (all-threo)
cis
cis
O
O
7
Hydrolisis
Based on these precedents, formation of 6 was intriguing and could be rationalised through a double
cis/trans-selective oxidative bis-cyclization process (Scheme 4). Each bis-cyclization event involves
three consecutive double bonds of the polyene chain starting from the terminal ones. In particular,
attack of RuO4 to the Δ2 double bond induces two successive cyclization steps giving rise to bis-THF
intermediate 8, in the same manner as shown for the synthesis of 1 (see intermediate 7, Scheme 3). A
second bis-cyclization would then occur at the other side of the molecule by attack of RuO4 at the
terminal, Δ22, double bond to give the all-threo tetra-THF 9 still possessing two oxoruthenate
appendages linked to C-11 and C-14. It can be presumed that a double substitution of the ruthenium-
containing portions, with inversion of configuration at involved carbon centres, would then occur
during the reductive quenching of the process, by iodide ions probably generated in situ by the action
of tiosulphate on iodate in turn produced during the oxidation of RuO2 to RuO4. It cannot be excluded
that iodide could originate from reduction of periodate itself not completely consumed in the reaction
medium. It is probable that such a side-process could be due to the higher concentration of the reaction
medium in the new experimented conditions [9].

Molecules 2011, 16
5365
Scheme 4. A plausible path for the formation of tetra-THF 6.
Oxidative
bis-cyclization
Oxidative
bis-cyclization
threo
threo
RuO2(cat.)/NaIO4
2
6
18
10
14
22
22
O
O
HO
H
H
HORuO3
Squalene
cis trans
8
RuO2
NaIO4
RuO2(cat.)/NaIO4
RuO4
NaIO3
Na2S2O3
Na2S2O3
erythro
threo
threo
threo
threo
threo
-
erythro
threo
I
1
3
10
O
6
O
14
11
14
O
I
11 I
O
O
SN2 at C-11
and C-14
Ru Species
O
O
O
HO
OH
OH
H
H
H
H
H
H
X
H
H
H
X
HO
H
trans
cis
6
cis trans
9 X= ORuO3
In order to enlarge the range of polyether substances accessible through the Ru-mediated
polycyclization process we began an exploration of the possible post-synthetic modifications of some
of the poly-THF backbones obtained through the above process. We have previously demonstrated that
progressive structural simplification of compound 1 to small-sized poly-THF compounds can be
achieved via an iterative PCC-mediated oxidative cleavage/reduction [7] sequence. The entire process
is possible due to the two alcohol functionalities adjacent to the terminal THF rings that are prone to be
intercepted by PCC [32]. In addition, a new type of cytotoxic spyroketal poly-THF compound, strictly
related to bis-spiroketals 2-5, could be accessed through a PCC-mediated oxidative spiroketalization
process starting from 1 [3]. In a more recent study we have also shown that the same oxidant, or the
related system PCC-H5IO6, is able to attack the angular CH position of the THF ring in various mono
and poly-THF substrates leading to either the oxidative opening of the THF ring or the oxidative
cleavage of suitable inter-THF bonds [33].
As a continuation of this project, we envisaged that compound 6, possessing a central bis-(α-iodo-
THF) portion, could be a good model compound to probe a double rearrangement-ring expansion
process involving the two internal THF rings as a means to access a new type of mixed THF-THP
polyether compounds further functionalised for successive synthetic manipulations providing access to
new polyether polycyclic materials. This type of reaction has previously been carried out on substances
containing a single α-iodo-THF subunit [34] but has never been attempted on a substrate containing
two α-iodo-THF moieties and, in particular, as far as we know, the double rearrangement-ring
expansion of a bis-THF substance has never been accomplished. Related chemistry has been
successfully employed for example in the synthesis of salynomicin [25] as well as in the synthesis of a
bis-oxepane portion of hemibrevetoxin [35]. Pleasingly, when compound 6 was reacted with excess
Ag2CO3 (5 equiv.) in acetone/water (8:2, 40 °C, 4 h), compound 10 was obtained in a 65% yield
demonstrating the feasibility of the projected transformation (Scheme 5).
Proof for the structure 10 was gained by chemical and high-field 2D-NMR evidence. Attempted
acetylation and benzoylation under standard conditions only delivered unreacted 10 indicating, as
expected, the presence of tertiary hydroxyl groups in this compound.

Molecules 2011, 16
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Scheme 5. Double rearrangement-ring expansion of compound 6.
1
A H1H-COSY experiment at 700 MHz indicated the presence in 10 of the two five-proton spin
systems H-3/H2-4/H2-5 and H-7/H2-8-H2-9 belonging to the two adjacent rings as well as the
H-11/H2-12 spin system. Assignment of each of these spin systems to the proper ring came from
considerations of spectral data and comparison with strictly related THF- and THP-containing
substances. In particular, the signals resonating at δ 3.86 and 2.36 were assigned, respectively, to the
angular THF proton (H-3) and to the Hα-5 proton based on the good agreement of their chemical shift
values with those typically exhibited by these protons in strictly analogous poly-THF substances
including the same cis-THF-containing substructure, previously synthesised in our laboratories [1-8].
This deduction suggested that the two higher field one-proton resonances at δ 3.26 (H-7) and 3.16
(H-11) could be ascribable to the angular hydrogens in the THP ring.
1
The good proton dispersion of the signals in the H-NMR spectrum of 10 allowed us to fully
analyse some crucial signals. In particular, the presence of a THP ring in 10 was corroborated by
J values (J = 12.5, 3.6 Hz) of the H-9 equatorial proton resonating as a clean double triplet at δ 1.89, as
expected for an equatorial proton next to a quaternary centre (C-10) in a six-membered ring possessing
a chair conformation. In addition, a W coupling observed between the signal at δ 1.54 for Hax-9 and
the singlet methyl resonance at δ 1.19, ascribable to the C-10 methyl group, also pointed to the
presence of a THP ring and the axial nature of that methyl. W-type long-range couplings were also
observed between the singlet resonances at δ 1.23 and 1.05 allowing assignment of these signals to the
two methyls belonging to the terminal 2-hydroxyisopropyl group. Similarly, a long-range coupling
between the methyl signal at δ 1.12 and the Ha-5 resonance at δ 2.36 allowed to assign the former
resonance to the angular methyl of the THF ring (C6-Me).
These conclusions were reinforced by data from a very informative 700 MHz NOESY experiment
(Figure 1) that also provided conclusive information on the relative configuration of the C-7, C-10 and
C-11 centres belonging to the THP ring in 10. In particular, the cis nature of the THP ring was inferred
by the presence of a strong correlation peak between signals for the H-7 and H-11 angular protons.
Similarly, the axial nature of the C-10 methyl, was further corroborated by a nOe correlation between
its resonance at δ 1.19 and that of the Hax-8 proton at δ 1.74. The rest of nOe cross peaks shown in
Figure 1 were in full agreement with the given stereostructure.

Molecules 2011, 16
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Figure 1. Summary of some significant 700 MHz NOESY correlations for compound 10
(due to the symmetry, half molecule is shown).
Me
H
H
H
H
H
Me
H
H
6
3
H
O
10
7
Me
O
OH
H
H
11
H
Me
OH
H
nOe
H
2.2. X-ray crystallography.
Molecules of 6 in the crystals are centrosymmetric (Ci point group) as they lie on crystallographic
inversion centres (Figure 2). The molecules have a stretched winding shape, which is due to the double
cis-trans sequence of the 2,5-disubstituted THF rings and to the trans-planar conformation of the
carbon chain.
The molecular conformation is stabilized by an intramolecular H bonding between O−H donor and
the oxygen acceptor of the inner THF ring (O1−H···O3 0.983, 2.224, 3.175(9) Å, 163°). Ring
puckering coordinates of the inner THF ring are q2 = 0.356(6) Å ϕ2 = 211(1)°, and of the outer are
q2 = 0.316(7) Å ϕ2 = 324(1)°. On the basis of the calculated phase angles, it can be argued that both are
basically in envelope conformation, with C7 and C4 atoms out of the envelope plane.
Figure 2. ORTEP view of 6.
The packing of molecules is accomplished through weak H bonding interactions between iodine
atoms as bifurcated acceptors and methyne C−H donors [36]. This is clearly shown in Figure 3. Chains
of H-bonded molecules are formed which run along b + c and b – c lattice directions. The weak
H-bonding leads to the formation of ring patterns having graph set descriptor R21 (7) . Along a
molecules are stacked in layers through van der Waals contacts.

Molecules 2011, 16
5368
Figure 3. Crystal packing of 6 viewed down b.
3. Experimental
3.1. General
All reagents were purchased (Aldrich) at the highest commercial quality and used without further
purification. Reactions were monitored by thin-layer chromatography carried out on precoated silica
gel plates (Merck 60, F254, 0.25 mm thick). Merck silica gel (Kieselgel 40, particle size 0.063-0.200
mm) was used for column chromatography. HPLC separations were carried out on a Varian 2510
apparatus equipped with a Waters R403 dual cell differential refractometer using Phenomenex
250 × 10 mm, Phenomenex 250 × 4.6 mm and Nucleosil 250 × 10 mm columns. NMR experiments
were performed on Varian Mercury Plus 400 MHz, Varian Unity Inova 700 MHz and Gemini 200
spectrometers in CDCl3. Proton chemical shifts were referenced to the residual CHCl3 signal
13
(7.26 ppm); C-NMR chemical shifts were referenced to the solvent (77.0 ppm). J values are in Hz.
Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. IR spectra were collected on a Jasco FT-IR-430 spectrometer. High Resolution MS spectra
were recorded on a Bruker APEX II FT-ICR mass spectrometer using the electrospray ionization (ESI)
technique in positive mode.
3.2. Synthesis
Squalene (50 g, 122 mmol) was placed into a 5 L round-bottomed flask equipped with a mechanical
stirrer and dissolved in the biphasic mixture EtOAc/CH3CN/H2O (3:3:2, 1.6 L). The solution was
cooled to 0 °C and NaIO4 (8 equiv., 976 mmol, 209 g) and RuO2•2H2O (20 mol%, 24.4 mmol, 3.25 g)
were sequentially added under vigorous stirring. After 30 min excess Na2S2O3•5H2O was added and
the mixture was stirred for further 10 min and then filtered through a Buchner funnel. The solid left on
the Buchner was thoroughly washed with EtOAc and the resulting biphasic solution was concentrated

Molecules 2011, 16
5369
in vacuo. The aqueous suspension was extracted with EtOAc (3 × 300 mL). The combined organic
phase was dried (Na2SO4) and evaporated in vacuo to give an oily product that was chromatographed
on silica gel (50 × 8 cm column) eluting with petroleum ether (40-70)/Et2O mixtures (from 7:3 to
100% ether) and then with CHCl3/MeOH mixtures (up to CHCl3/MeOH 8:2) to give three fractions:
fraction A (7.40 g) eluted before penta-THF 1; fraction B (4.75 g) containing penta–THF 1 and
fraction C (35.18 g) eluted after penta-THF 1. A sample (500 mg) of the less polar fraction A was
separated by HPLC (250×10 mm column, eluent: hexane-EtOAc, 8:2, flow 2.5 mL/min) to give
previously isolated bis-spiroketals 2-5. The fraction eluted in the range 20-30 min was subjected to a
further reversed-phase HPLC separation (250×10 mm column; flow: 1.0 mL/min, eluent: MeOH/H2O,
8:2, tR = 14.5 min) to give pure 2,2'-(5',5''-(1,4-diiodobutane-1,4-diyl)bis(2,5'-dimethyl-octahydro-2,2'-
bifuran-5',5-diyl))dipropan-2-ol (6, 2.5 mg, 0.03%). IR (neat): νmax 3706, 3780, 1054, 1013 cm-1; 1H-
NMR: (400 MHz, CDCl3) δ 4.00 (1H, bd, J = 9.7), 3.91 (1H, m), 3.85 (1H, dd, J = 7.7, 5.2), 2.32 (1H,
m), 2.23 (1H, ddd, J = 12.1, 8.7, 8.7), 1.45, 1.25, 1.13, 1.09 (3H each, s’s, 4xMe); 13C-NMR (50 MHz,
CDCl3): δ 85.6, 85.0, 84.4, 83.0, 71.9, 47.9, 39.9, 36.4, 34.7, 27.9, 27.2, 25.8, 24.9, 24.3, 22.9; HRMS
(ESI) m/z calcd for C30H52I2NaO6 [M+Na]+ 785.1751, found 785.1748.
3.3. Ring expansion of 6 to 10
To compound 6 (1.5 mg, 0.02 mmol) dissolved in acetone-water (4:1, 500 μL) was added silver
carbonate (16.8 mg, 0.1 mmol) and the mixture stirred at 40 °C. After 4h, the mixture was filtered and
the solid thoroughly washed with acetone. The organic phase was taken to dryness to give an oily
product. HPLC purification (250 × 4.6 mm column; flow: 1.0 mL/min; CHCl3MeOH, 98:2) gave pure
2,2'-(butane-1,4-diyl)bis(6-(5-(2-hydroxypropan-2-yl)-2-methyl-tetrahydrofuran-2-yl)-3-methyl-
1
tetrahydro-2H-pyran-3-ol) (10, 0.7 mg, 65%, tR =16.5 min). Oil; IR (neat): νmax 3440 cm-1; H-NMR:
(700 MHz, CDCl3) δ 3.86 (1H, dd, J = 8.4, 3.7), 3.26 (1H, bdd, J = 7.0, 7.0), 3.16 (1H, bd, J = 6.3),
2.36 (1H, ddd, J = 10.0, 10.0, 10.0), 2.05 (1H, dddd, J = 12.7, 9.6, 3.7, 3.7), 2.03-1.94 (2H, m), 1.89
(1H, ddd, J = 12.5, 3.6, 3.6), 1.75 (2H, m), 1.54 (2H, m), 1.31 (1H, m), 1.23, 1.19, 1.12, 1.05 (3H each,
s’s, 4 × Me); HRMS (ESI) m/z calcd for C30H54NaO8 [M+Na]+ 565.3716, found 565.3710.
3.4. X-Ray Crystallography
Crystals of 6 suitable for X-ray analysis were obtained from CHCl3 by slow evaporation of the
solvent. Data were collected at 298 K on a Bruker-Nonius Kappa-CCD diffractometer using graphite
monochromated MoKα radiation (λ = 0.71073 Å). Data reduction and multi-scan absorption correction
were done using SADABS program [37]. The structure was solved by direct methods (SIR97 program
[38]) and refined by the full matrix least-squares method on F2 using SHELXL-97 program [39] with
the aid of the program WinGX [40]. Non-hydrogen atoms were refined anisotropically. H atoms of the
hydroxy group was located in difference Fourier maps and refined with Uiso = 1.2·Ueq of the carrier
atom. The positions of the other H atoms were determined stereochemically and refined by the riding
model with Uiso = 1.2·Ueq of the carrier atom (1.5·Ueq for H atoms of methyl groups). Ring puckering
coordinates [41] were determined using the program PARST [42]. The analysis of the crystal packing
and the drawing of the molecule were performed using the programs Mercury [43] and ORTEP [44].

Molecules 2011, 16
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Crystal and refinement data are summarized in Table 1. CCDC reference number 821334 contains the
supplementary crystallographic data for 6.
4. Conclusion
In conclusion, the isolation of bis-iodocompound 6 was interesting from both a mechanistic and a
synthetic point of view. Its existence among the oxidation products of squalene with RuO4 was
indicative of the existence of an intermediate species (see 9, Scheme 4), carrying oxoruthenium
substituents, likely ORuO3 groups, adjacent to the two internal THF rings, able to undergo a facile
nucleophilic displacement, that enforces the mechanistic hypothesis previously put forward to explain
the formation of penta-THF 1 from the same substrate (Scheme 3). In addition, the postulated
mechanism for the formation of 6 also suggests a new possible use of the RuO4-catalysed
polycyclization process where suitable polyenes can be induced to undergo bidirectional poly-THF-
forming oxidative sequences. The facile access to a novel type of bis-THF-bis-THP compound (10)
has been demonstrated via a double ring-enlargement process. Studies are in progress to further
develop the chemistry presented here toward the synthesis of new THP-containing polyether
compounds.
Acknowledgments
We are grateful to the “Centro di Metodologie Chimico-Fisiche” and the “Centro di Servizio
Interdipartimentale di Analisi Strumentale” (CSIAS) of the University of Napoli “Federico II” for
NMR facilities.
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Sample Availability: Samples of the compounds 6 and 10 are available from the authors
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