Cis,cis,cis,cis-1,2,3,4,5-Pentakis(hydroxymethyl)cyclopentane

Article abstract of DOI:10.1016/j.tet.2013.08.013

All-cis pentamethanolcyclopentane has been obtained in six steps by Diels-Alder condensation of maleic anhydride with (benzyloxymethyl)cyclopenta-2, 4-diene, reduction of the anhydride to a diol that was protected as the acetonide. Then, ozonolysis of the double bond, followed by reduction led to a cis-diol. Then successive deprotections of the three other methanol groups gave the cis,cis,cis,cis-1,2,3,4,5-pentakis(hydroxymethyl)cyclopentane.

Full text of DOI:10.1016/j.tet.2013.08.013

Accepted Manuscript
Cis,cis,cis,cis-1,2,3,4,5-pentakis(hydroxymethyl)cyclopentane
Adeline R. Pujol, Nicolas Ratel-Ramond, André Gourdon
PII:
S0040-4020(13)01287-8
10.1016/j.tet.2013.08.013
TET 24702
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 June 2013
Accepted Date: 9 August 2013
Please cite this article as: Pujol AR, Ratel-Ramond N, Gourdon A, Cis,cis,cis,cis-1,2,3,4,5-
pentakis(hydroxymethyl)cyclopentane, Tetrahedron (2013), doi: 10.1016/j.tet.2013.08.013.
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Cis,cis,cis,cis-1,2,3,4,5-
pentakis(hydroxymethyl)cyclopentane
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Adeline R. Pujol, Nicolas Ratel-Ramond and André Gourdon
NanoSciences Group, CEMES-CNRS, 29 rue Jeanne Marvig BP 94347, 31055 Toulouse Cedex 4 (France)

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Tetrahedron
journal homepage: www.elsevier.com
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Cis,cis,cis,cis-1,2,3,4,5-pentakis(hydroxymethyl)cyclopentane
Adeline R. Pujol,a, b Nicolas Ratel-Ramonda and André Gourdon*,a
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a NanoSciences Group, CEMES-CNRS, 29 rue Jeanne Marvig, BP 94347, 31055 Toulouse Cedex 4, France
b Université de Toulouse, UPS, 118 route de Narbonne, F-31062 Toulouse cedex 9, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
All-cis pentamethanolcyclopentane has been obtained in six steps by Diels-Alder condensation
of maleic anhydride with (benzyloxymethyl)cyclopenta-2,4-diene, reduction of the anhydride to
a diol that was protected as the acetonide. Then, ozonolysis of the double bond, followed by
reduction led to a cis-diol. Then successive deprotections of the three other methanol groups
gave the cis,cis,cis,cis-1,2,3,4,5-pentakis(hydroxymethyl)cyclopentane.
Available online
Keywords:
alcohols
cycloaddition
ozonolysis
diastereoselectivity
2009 Elsevier Ltd. All rights reserved.
____
1. Introduction
A particular attention has been paid in the last decade to the
32 non-pyrolytic synthesis of buckybowls.1 These bowl-shaped
polycyclic aromatic hydrocarbons (PAH) are not only considered
as potential precursors for the rationale synthesis of fullerenes
and short nanotubes, but also as new materials with attractive
properties like molecular receptors, or precursors of clips and
tweezers. So far, all published syntheses of fullerene related
buckybowls like corannulenes, or of precursors for the
preparation of C60 by Flash Vapor Pyrolysis2 start from planar,
low symmetry, benzenoids molecules. However, passing from a
planar benzenoid system to a curved one is an energetically
expensive process3 requiring high temperatures (like in FVP) or
pre-twisted sterically crowded precursors.4 Furthermore, these
bowl-shaped molecules comprise a five-membered ring in their
core which in general requires multiple synthetic steps that do not
take into account the C5 symmetry of the final target.
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Scheme 1. Cis,cis,cis,cis-1,2,3,4,5 pentakis(hydroxymethyl)-
cyclopentane 1.
This compound has been previously reported by Tolbert et al5
in a short communication without any experimental details which
led us to reinvestigate its preparation.
2. Results and Discussion
In the course of an exploration of alternative methods to
synthesise new buckybowls, like pentabenzocorannulenes, we
envisioned that an attractive route would require the preparation
of an all-cis adduct of cyclopentane, followed by steps fully
Scheme 2 outlines our retrosynthetic analysis of 1, similar to that
of ref. 5. We planned to use as a key product the Diels-Alder
adduct 2, bearing of the same side of a cyclopentane ring, a
protected alcohol, and an alkene function and an anhydride as
synthetic equivalents of the four other methanol substituents.
51 using the C5 symmetry of this adduct without building-up the
strain induced by curvature. After completion of the carbon
skeleton, the foreseen final step of the synthesis would be
aromatization by dehydrogenation. This objective led us to
consider the bowl-shaped all-cis cyclopentanepentamethanol 1 as
an attractive intermediate target (scheme 1).
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---------
*Corresponding author. Email:andre.gourdon@cemes.fr
Scheme 2. Retrosynthetic analysis for the preparation of 1.

2
Tetrahedron
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An analogous strategy has been used by Wu6 and Mehta7 for the
benzylether,12 and that the formed pentaalcohol 1 cannot be
synthesis of pentaoxa[5]peristylane, oxa bowls with a crown-like
shape, starting from a norbornyl framework with the appropriate
stereochemical features bearing latent aldehyde functionalities.
First we investigated the Diels-Alder condensation of maleic
anhydride with (benzyloxymethyl)cyclopenta-2,4-diene in
various conditions (scheme 3). The latter compound can be
extracted as it is soluble in water and also possibly trapped in
lithium salts. Reduction with sodium borohydride in place of
LiAlH4 did not provided the diol as expected but gave two
lactones 5 and 6 in ca 10% yields (scheme 4).
1
2
3
The structure of compound
crystallography (Fig. 1).
5 was confirmed by X-ray
4
obtained
by
alkylation
of
cyclopentadienide
by
5
6
7
8
benzylchloromethyl ether at low temperature. This step is often
hindered by the formation of a significant amount of double-bond
isomerized side products. Previous works8,9 have shown that
isomerization could be avoided by the use of thallous
9
cyclopentadienide
instead
of
sodium
or
potassium
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cyclopentadienide. Diels-Alder addition of TlCp with maleic
anhydride in ether gave a mixture of endo 2 and exo 3, in the
ratio 98:2, in 63% yield (scheme 3). 2 can be purified by
successive recrystallization in ether or by silica gel
chromatography, whereas 3 is a viscous liquid. In order to avoid
the use of toxic thallium compounds, we also explored this
synthesis starting from sodium cyclopentadienide in DMF as
suggested by Gellman et al.10 After extraction of
(benzyloxymethyl)cyclopenta-2,4-diene in cold pentane, Diels-
Alder addition in ether gave similar yield as the procedure using
thallium. Finally, 2 can also be obtained even more conveniently
by a one-pot procedure in DMF, without extraction and
purification step of the cyclopentadiene adduct, and with similar
yields.
Figure 1. X-ray structure of 5. The angle between the lactone
planes is 61° and the cyclopentane ring is nearly planar with
deviations from the mean plane below 0.15 Å.
The formation mechanism of these two lactones can be
rationalized by analogy with similar ozonolyses followed by
reduction with sodium borohydride of strained molecules
(scheme 5) 13,14,15
.
Scheme 3. Procedure 1 (TlCp): a) C6H5CH2OCH2Cl, Et2O, -20°C
b) Maleic anhydride, Et2O, 0°C. Procedure
2 (NaCp):
C6H5CH2OCH2Cl, DMF, -40°C b) Maleic anhydride, Et2O, -5°C.
Procedure 3 (NaCp) one-pot: a) C6H5CH2OCH2Cl, DMF, -40°C
b) Maleic anhydride, -5°C.
Scheme 5. Ozonolysis of 4 and first steps of the reduction.
According to the Criegee's mechanism, after the first step of
addition of O3 to give the primary ozonide I, this latter rearranges
to form a carbonyl and a carbonyl oxide. This oxide undergoes an
intramolecular 1,3 dipolar addition either to the aldehyde, either
to the ester group carbonyl to give respectively the ozonide II a
and b. Reductions of these ozonides by sodium borohydride give
the intermediate dialdehyde. Then the borohydride reacts with
one of the aldehyde to form in a first step a sodium alcoholate.
This latter can either attack the ester carbonyl group, either the
second aldehyde according to the mechanisms shown below in
schemes 6 and 7, respectively.
Scheme 4. c) MeOH, HCl d) O3, DCM, -60°C; NaBH4, EtOH.
Since direct ozonation/reduction of strained norbornene
dicarboxylic anhydride derivatives is known to give numerous
by-products,11 the ozonation was carried out from the diester 4,
obtained from 2 in nearly quantitative yield by esterification of
the anhydride. Attempts to reduce the ozonide with lithium
aluminium hydride to obtain directly the tetra-alcohol were
unsuccessful. One hypothesis is that the ozonolysis deprotects the

3
yield. Finally, deprotection of the fifth alcohol function was
ACCEPTED MANUSCRIPT
done by hydrogenolysis over Pd/C catalyst to yield 1 in 90 %
yields (scheme 9).
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Scheme 6. Double intramolecular nucleophilic attacks of the
neighbour ester carbonyl groups to give the symmetrical
compound 5.
Scheme 9. h) O3, DCM; NaBH4, EtOH i) Amberlite 120,
H2O/THF j) H2, Pd/C.
In the case of nucleophilic attack of the neighbour ester, both
reactions are parallel involving the loss of two sodium
methanolate leading to the intramolecular bi-lactone 5. In
contrast, the intramolecular nucleophilic attack of the aldehyde
gives the compound 6 (scheme 7).
1 is a colourless viscous oil soluble in methanol and water. The
NMR analysis of 1 are consistent with a C5 symmetric structure
1
with only two peaks in H and 13C NMR corresponding to the
CH2 and CH groups
3. Conclusions and perspectives
To sum up, we have obtained the all-cis pentamethanol-
cyclopentane 1 in seven steps from sodium cyclopentadienide
and a total yield around 10%. This five-fold symmetry compound
is an interesting starting point for further functionalization
towards buckybowls or towards pentatopic ligands.
4. Experimental section
Scheme 7. Intramolecular nucleophilic attacks of the carbonyl
group to give the compound 6.
Hydrochloric acid was prepared by addition of concentrated
sulphuric acid to ammonium chloride. Benzyl chloromethyl ether
was synthesized according to reference 18. Thallium
cyclopentadienide was prepared from thallium sulfate (reference
19). Sodium cyclopentadienide (2M solution in THF), was from
Aldrich. Et2O, DCM, MeOH and THF were dried over molecular
sieves prior to use. THF was distilled from Na/benzophenone.
DMF was from Aldrich or Acros Organics. Flash column
chromatography was performed by using silica gel (60 Å pore
size, 40–63 μm, Merck). The reactions were monitored by thin
layer chromatography (TLC) on silica gel-coated plates (Merck
60 F254). Detection was performed by using UV light and by
charring the plate at ca. 150 °C, after dipping it into an ethanolic
solution of phosphomolybdic acid (PMA). The yields refer to
chromatographically and spectroscopically (1H and 13C NMR)
homogeneous material, unless otherwise stated. The NMR
spectroscopic data were recorded with Bruker Avance 300 /400/
500 instruments and are calibrated by using the residual
undeuterated solvent as an internal reference (CD2Cl2 H: 5.32
ppm,C: 53.8 ppm; MeOD: H: 3.31 ppm, C: 49.0 ppm).
Chemical shifts are reported in ppm on the δ scale and coupling
constants, J, are in Hz. The abbreviations used to explain
multiplicities are s = singlet, d = doublet, t= triplet, m =
multiplet, br. = broad. Mass spectra were obtained in the CI mode
with Nermag R10-R10. High Resolution Mass Spectra (HRMS)
were obtained with GCT 1er Waters. Elemental analyses were
done by the Service d’Analyse de l'ICSN (Paris). X-ray structure
analysis
This observation led us finally to follow the route proposed by
Doucet
and
Santelli16
to
prepare
the
ligands
tetrakis(diphenylphosphinomethyl)cyclopentane (Tedicyp). First,
reduction of the anhydride 2 by LiAlH4 gave the diol 7 in very
good yields. 7 was protected as the acetonide 8 using a large
excess of 2-methoxypropene and
a catalytic amount of
camphorsulfonic acid.17 Surprisingly, the use of p-toluenesulfonic
acid as a catalyst16 in similar conditions favoured the dehydration
to give the ether 9 (scheme 8).
Scheme 8. e) LiAlH4, THF/Et2O f) MeC(OMe)CH2, cat CSA,
DCM, h) MeC(OMe)CH2, cat TsOH, DCM.
Ozonation of 8, followed by reduction by sodium borohydride
gave the diol 10 in 33 % yield which was then hydrolyzed by
water in tetrahydrofuran in the presence of a strong acidic action
exchange resin (Amberlite-IR 120) to give the tetra-ol 11 in 90 %

4
Tetrahedron
ACCEPTED MANUSCRIPT
Data for X-ray single crystal structure determination were
anhydride (1.742 g, 17.8 mmol, 1.1 eq) and DMF (10 mL) were
collected with a Enraf Kappa-CCD automatic X-ray single-
crystal diffractometer, using Mo Kα radiation, for which a
graphite monochromator was used. Intensities were measured
using an Apex2 detector at sample-to-detector distance of 50 mm
and at a temperature of 293 K. The crystallographic cell was
found using EVAL-CCD.20 The point group determination was
followed by the determination of the position of all non-hydrogen
atoms by direct methods using SIR200421 and refined in the
WinGX software package20 using SHELX-97.23 Absorption
the added and the mixture was maintained under vigorous stirring
at -20°C for 20 min and at -5°C overnight. Then, 40 mL of water
and 40 mL of dichloromethane were added to the mixture. The
organic phase was separated, washed with water (3 x 40 mL) and
dried over magnesium sulfate. After filtration, the solvents were
evaporated. Addition of diethyl ether (20 ml) to the residue left a
precipitate which was filtered and washed with cold diethyl ether.
Yield = 63 % (endo/exo 98:2). The separation of isomers is
identical to that of the procedure 1.
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corrections were performed using the SADABS program.24,
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CCDC-897129 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Compound 2
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Cambridge
www.ccdc.iucr.uk/data_request/cif.
Crystallographic
Data
Centre
via
1H NMR (300 MHz, CD2Cl2): δ = 7.33 (m, 5H), 6.19 (m, 2H),
4.42 (s, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 3.35 (d, J = 7 Hz, 2H),
2.35 (m, 1H). 13C NMR (75 MHz, CD2Cl2): δ = 171.5 (Cqester),
138.8 (Cqaro), 133.2 (=CH), 128.6 (CHaro), 127.9 (CHaro),
127.8 (CHaro), 73.3 (CH2), 67.1 (CH2), 64.5 (CH); 48.0 (CH),
47.4 (CH). MS (NH3): calcd. for C17H20NO4 [M+NH4]+: 302.14;
found: 302.0. Anal. Calcd. for C17H16O: C, 71.82; H, 5.67; found:
C, 71.51; H, 5.77.
Caution: Thallium salts are exceedingly toxic and should be
handled with due care by skilled chemists.
4.1. Compounds 2 and 3.
Procedure
1
from
cyclopentadienylthallium:
Cyclopentadienylthallium (16.70 g, 62 mmol, 1 eq) was added to
solution of benzylchloromethyl ether (10.6 mL, 76.2 mmol, 1.23
eq) in anhydrous diethyl ether (50 mL) at -20°C. The mixture
was stirred overnight at this temperature and filtered on cold
celite. The precipitate was washed with cold diethyl ether (3 x 30
mL at -20°C) and to the filtrate was added by portions 1.2
equivalent of maleic anhydride (7.416 g, 75.6 mmol). The
mixture was kept under stirred -10°C for 8 h, and then overnight
at 0°C. The after cooling back to -10°C, the suspension was
filtered. The precipitate was washed with cold ether and
recrystallized in diethyl ether. The precipitate (yield = 63 %) is a
mixture of endo 2 and exo 3 (98:2). The endo form 2 can be
purified by successive recrystallizations in diethyl ether, the
mother liquors being enriched in exo form 3 which is oily. These
isomers can also be purified by silica gel column
chromatography (petroleum ether / dichloromethane/ ethyl
acetate 70: 24: 6).
Compound 3
1H NMR (300 MHz, CD2Cl2): δ = 7.33 (m, 5H), 6.36 (m, 2H),
4.46 (s, 2H), 3.50 (m, 2H), 3.35 (m, 2H), 3.23 (d, J = 7 Hz, 2H),
2.42 (m, 1H). 13C NMR (300 MHz, CD2Cl2): δ = 171.9 (Cqester),
138.4 (Cqaro), 137.2 (=CH), 128.8 (CHaro), 128.1 (CHaro),
128.8 (CHaro), 73.5 (CH2), 68.0 (CH2), 64.6 (CH); 47.3 (CH),
45.9 (CH). MS (NH3): calcd. for C17H20NO4 [M+NH4]+: 302.14;
found: 302.2.
4.2. Endo-dimethyl 7-anti-
(phenylmethoxy)methylbicyclo[2.2.1]hept-5-ene-2,3-
dicarboxylate compound (4)
Hydrochloric acid, prepared from 1.7 mL (32 mmol) of
concentrated sulphuric acid and 1.7 g (32 mmol) of ammonium
chloride, was bubbled in a suspension of 2 (4.6 g, 126 mmol) in
anhydrous methanol (100 mL). When the precipitate started
solubilizing, the mixture was heated at 75°C for 1 h. After
cooling to RT, the solvent was evaporated. The residue was
dissolved in diethyl ether (20 mL) to which was added a
saturated solution of NaHCO3. The organic phase was then
washed with brine, dried over MgSO4, filtered and concentrated
under vacuum. The residue was purified by silica gel column
chromatography (hexane/dichloromethane (80-100%) and then
DCM /AcOEt (0-10%)). The compound was obtained as a
colorless oil (yield = 63 %). TLC (dichloromethane/ethyl acetate
Procedure 2 from sodium cyclopentadienide: To a solution of
benzylchloromethyl ether (4.4 mL, 31.6 mmol, 2 eq) in 40 mL of
40 anhydrous DMF at -40°C was added drop wise 8 mL of a 2M
solution of sodium cyclopentadienide in THF (16 mmol, 1 eq).
The mixture was maintained under vigorous stirring at -40°C for
20 min, and then poured into a cold (4°C) mixture of pentane
(120 mL) and water (60 mL). After extraction with cold pentane
(2 x 60 mL), and the grouped organic phases were washed with
icy water (2 x 60 mL), the dried over magnesium sulfate and
filtered. The pentane was removed by distillation under reduced
pressure at 0°C. The cold yellow oily residue was dissolved in 18
mL of diethyl ether at -5°C, and maleic anhydride (1.71 g, 17.4
mmol, 1.1 eq) was added by portions. The mixture was stirred at
-20°C for 30 min, and then at -5°C overnight. The precipitate was
washed with cold ether and the purification steps were similar to
the one in procedure 1. Yield = 62 % (endo/exo 98:2).
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9:1) Rf: 0.6. H NMR (300 MHz, CD2Cl2): δ = 7.32 (m, 5Haro),
6.12 (m, 2H), 4.43 (s, CH2-O), 3.58 (s, 2 CH3), 3.39 (d, J = 7Hz,
2H), 3.35 (m, 2H), 3.12 (m, 2H), 2.14 (t, J = 7 Hz, 1H). 13C NMR
(300 MHz, CD2Cl2): δ = 172.6 (Cqester), 139.1 (Cqaro), 132.6
(=CH), 128.6 (CHaro), 127.8 (CHaro), 73.2 (Ph-CH2-O), 67.8
(CH2-O), 60.1 (CH), 51.6 (CH3), 48.9 (CH), 48.5 (CH). HRMS
(DCI CH4): calcd. for C19H23O5 [M+H]+: 331.1545; found:
331.1535.
Compounds 2 and 3. Procedure 3: one-pot from sodium
cyclopentadienide: To a solution of benzylchloromethyl ether
(4.4 mL, 31.6 mmol, 2 eq) in 40 mL of anhydrous DMF at -40°C
was added drop wise 8 mL of a 2M solution of sodium
cyclopentadienide in THF (16 mmol, 1 eq). The mixture was
maintained under vigorous stirring at -40°C for 20 min. Maleic
4.3. Compounds 5 and 6
Ozone in air was bubbled in a solution of 4 (204 mg, 0.6
mmol, 1 eq) in 7 mL of anhydrous dichloromethane at -60°C.
The reaction was monitored by TLC. Then argon was purged

5
through to remove any excess of ozone, followed by addition of 6
mL of ethanol at -60°C and 120 mg of NaBH4 (3.17 mmol, 5
eq.). The suspension was stirred overnight at room temperature.
Then, 10 mL of brine and 20 mL of ethyl acetate were added.
The organic phase was separated and the aqueous phase was
extracted with ethyl acetate (3 x 10 mL). The grouped organic
phases were then washed with water (10 mL), dried over
magnesium sulfate and filtered. After evaporation of the solvents,
the residue is purified by successive silica gel chromatography
(Pet. Eth./ AcOEt). 5 is obtained as colorless crystals (yield =
11%) and 6 is a colorless oil (yield = 10%).
13C NMR (75 MHz, CD Cl ): δ = 139.1 (Cqaro), 132.6 (=CH),
2 2
ACCEPTED MANUSCRIPT
128.5 (CHaro), 127.8 (CHaro), 127.7 (CHaro), 73.1 (CH2), 68.3
(CH2), 62.7 (CH2), 61.2 (CH), 48.6 (CH), 46.1 (CH). MS (DCI
NH3): calcd for C17H23O3 [M+H]+ 275.2; found: 275.1. HRMS
(DCI CH4): calcd for C17H23O3 [M+H]+: 275.1647; found:
275.1659.
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4.6. Cis-endo-2,3-Bis(hydroxymethyl)-7-anti-
(phenylmethoxy)methylbicyclo[2.2.1]-hept-5-ene acetonide
(8)
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A large excess of methoxypropene (3.6 mL, 37.6 mmol, 7.4
eq) and a catalytic amount of camphorsulfonic acid (83 mg, 0.36
mmol, 0.07 eq) were added to a solution of 7 (1.40 g, 5.11 mmol,
1 eq) in anhydrous dichloromethane (15 mL) at 0°C. At the
addition of methoxypropene, the mixture turned brown. The
mixture was stirred at room temperature for 6 h. Then potassium
carbonate (60 mg, 007 eq) was added, and the yellow mixture
was stirred 1 h, filtered and concentrated under vacuum. Column
chromatography (petroleum ether/ ethyl acetate 0-5%) provided 8
as an oil containing a yellow impurity. The product was used as
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Compound 5:
1H NMR (400 MHz, CD2Cl2): δ = 7.33 (m, 5H); 4.49 (s, 2H);
13 4.33-4.25 (m, 2H), 4.20-4.13 (m, 2H), 3.58 (d, J = 7 Hz, 2H),
14 3.33 (m, 4H), 2.91 (m, 1H). 13C NMR (100 MHz, CD2Cl2): δ =
175.7 (Cqlactone), 138.0 (Cqaro), 128.8 (CHaro), 128.3 (CHaro),
128.2 (CHaro), 73.8 (CH2), 68.2 (CH2), 67.5 (CH2), 47.5 (CH),
44.6 (CH), 43.4 (CH). MS (DCI NH3): calcd for C17H22NO5
[M+NH4]+ 320.1; found: 320.1. HRMS (DCI CH4): calcd for
C17H19O5 [M+H]+: 303.1232; found: 303.1241.
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1
such for the next step. TLC (DCM/AcOEt 9:1): Rf = 0.4. H
NMR (500 MHz, CD2Cl2): δ 7.36 (m, 5H), 6.04 (m, 2H), 4.45 (s,
2H), 3.70 (m, 2H), 3.48 (m, 2H), 3.40 (d, J= 7Hz, 2H), 2.74 (m,
2H), 2.70 (m, 2H), 2.32 (m, 1H), 1.37 (s, 6H). 13C (125 MHz,
CD2Cl2): δ = 139.4 (Cqaro), 132.8 (=CH), 128.6 (CHaro), 127.8
(CHaro), 127.7 (CHaro), 101.3 (Cq), 73.1 (CH2), 68.2 (CH2),
64.8 (CH2), 63.0 (CH), 47.9 (CH), 46.4 (CH), 30.2 (CH3), 19.9
(CH3). MS (DCI NH3): calcd. for C20H30NO3 [M+NH4]+: 332.2;
found: 332.2.
X-ray Crystal Structure analysis for 5: formula C17H18O5, Mw
= 302.3, colorless crystal, a = 9.307(6) Å, b = 13.079(9) Å, c =
12.512(4) Å, = 109.16(3)°, V = 1438 Å3, calc = 1.396,  = 0.1
mm-1, no absorption correction, Z = 4, monoclinic, space group
P21/c (n° 14), = 0.71069 Å, T = 300 K, 16265 reflections
collected, 2384 independent observed reflections [I≥2(I)], 218
refined parameters, R = 0.052, wR2 = 0.113, max; (min.) residual
electron density 0.3 (-0.19) e. Å-3.
4.7. Compound 9
4.4. Compound 6:
To a solution of 7 (85 mg, 0.31 mmol) under argon in
anhydrous dichloromethane (6 mL) were added a large excess of
methoxypropene (0.17 mL, 1.38 mmol, 4.5 eq) and a catalytic
amount of p-toluenesulfonic acid (3 mg, 17 mol, 0.06 eq.) and
113 mg of molecular sieves. The mixture was refluxed for 2 h
and cooled to RT. After addition of potassium carbonate (44 mg),
the mixture was filtered over celite, and after evaporation of the
solvent, chromatographied on silica gel using a mixture of
dichloromethane and ethyl acetate (0 to 100%) as eluent. 9 is an
1H NMR (500 MHz, CD2Cl2): δ = 7.36-7.30 (m, 5H); 5.73 (d,
J = 7Hz, 1H), 4,54 (s, 2H), 4.28 (d, J = 13 Hz, 1H), 3.95 (dd, J =
12 Hz, 8 Hz, 1H), 3.85 (m, 2H), 3.69 (s, 3H), 3.20-3.10 (m, 2H),
3.10-3.00 (m, 1H), 2.62-2.57 (m, 1H), 2.22 (m, 1H). 13C NMR
(125 MHz, CD2Cl2): δ = 175.7 (Cq), 170.8(Cq), 138.7 (Cqaro),
128.7 (CHaro), 128.0 (CHaro), 101.7 (CH), 73.5 (CH2), 67.6
(CH2), 61.8 (CH2), 52.2 (CH), 49.5 (CH), 43.3 (CH), 43.1 (CH),
42.7 (CH), 38.1 (CH). MS (DCI NH3): calcd for C18H24NO6
[M+NH4]+ 350.2; found 350.1. HRMS (DCI CH4): calcd for
C18H21O6 [M+H]+: 333.1338; found: 333.1349.
1
unstable yellow oil that decomposes over time at RT. H NMR
(300 MHz, CD2Cl2): δ = 7.30 (m, 5H), 6.06 (m, J = 2 Hz, 2H),
4.40 (s, 2H), 3.54-3.46 (m, 2H), 3.39 (dd, J = 9 Hz, 2 Hz, 2 H),
3.35 (d, J = 7 Hz, 2 H), 2.93 (m, 2H), 2.82 (m, 2H), 2.27 (m, J =
7Hz, 1H). 13C NMR was not recorded due to decomposition of
the compound. HRMS (DCI CH4): calcd for C17H21O2 [M+H]+:
257.1542; found: 257.1549.
4.5. Cis-endo-2,3-Bis(hydroxymethyl)-7-anti-
(phenylmethoxy)methylbicyclo[2.2.1]-hept-5-ene (7)
Under argon, a solution of 2 (1.808 g, 6.36 mmol, 1 eq) in 10
mL anhydrous THF was added dropwise to a suspension of
LiAlH4 (680 mg, 17.9 mmol, 2.9 eq) in 12 mL of anhydrous
4.8. (7-(phenylmethoxy)methyl-3,3-dimethylhexahydro-1H-
cyclopenta[e][1,3]-dioxepine-6,8-diyl)dimethanol (10)
49 diethyl ether. The mixture was refluxed 1.5 h. After cooling to
RT, were added successively: 0.7 mL of icy water, 0.7 mL of a
1M aqueous solution of NaOH, and 3 x 0.7 mL of distilled water.
The mixture was stirred for 1 h and filtered. The precipitate was
washed with 30 mL of chloroform, and 10 mL of water were
added to the filtrate. The aqueous phase is extracted with 2 x 25
mL of chloroform and the grouped organic phases were dried
over MgSO4. After solvent removal, the raw product was
purified by column chromatography (dichloromethane/ethyl
acetate 0-100%). 7 is a colorless oil (yield = 89 %). TLC
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54
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56
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61
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Ozone in air was bubbled through a solution of 8 (1.10 g, 3.5
mmol, 1 eq) in 20 mL of anhydrous dichloromethane at -60°C.
Then argon was purged through to remove any excess of ozone,
followed by addition of 3 mL of ethanol and 400 mg of NaBH4
(10.6 mmol, 3 eq). The mixture was stirred at room temperature
for 6 h. After addition of 15 mL of water, the organic phase was
separated and the aqueous phase was extracted with
dichloromethane (3 x 20 mL). The grouped organic phases were
dried (MgSO4) and concentrated under vacuum. The raw product
was purified by column chromatography (dichloromethane/ethyl
acetate 0-60%) giving 10 as a colorless oil (yield = 33%). TLC
1
(AcOEt): Rf = 0.5. H NMR (300 MHz, CD2Cl2): δ = 7.37 (m,
5H), 5.97 (m, 2H), 4.71 (br, 1H), 4.46 (s, 2H), 3.58-3.34 (m, 4H),
3.42 (d, J = 7Hz, 2H), 2.83 (m, 2H), 2.59 (m, 2H), 2.24 (m, 1H).

6
Tetrahedron
(DCM/AcOEt 4:6): Rf = 0.3-0.4. 1H NMR (500 MHz, CD Cl ):
References and notes
ACCEPTED MANUSCRIPT
2
2
δ = 7.35 (m, 5H), 4.53 (s, 2H), 3.81-3.60 (m, 8H), 3.74 (d, J=
7Hz, 2H), 2.66 (m, 1H), 2.47 (m, 2H), 2.29 (m, 2H), 1.31 (s, 3H),
1.28 (s, 3H). 13C NMR (125 MHz, CD2Cl2): δ = 138.1 (Cqaro),
128.8 (CHaro), 128.3 (CHaro), 128.2 (CHaro), 102.2 (Cq), 73.8
(CH2), 71.0 (CH2), 61.2 (CH2-O), 60.9 (CH2-O), 46.3 (CH), 45.8
(CH), 43.0 (CH), 24.8 (CH3), 24.5 (CH3). MS (DCI NH3): calcd.
for C20H31O5 [M+H]+: 351.2; found 351.2.
1.
A. Sygula, Eur. J. Org. Chem. 2011, 2011, 1611-1625.
2. M. A. Kabdulov, K. Y. Amsharov, M. Jansen, Tetrahedron 2010,
66, 8587-8593.
3. M. A. Kabdulov, K. Y. Amsharov, M. Jansen, Tetrahedron 2010,
66, 8587-8593.
4. A. Sygula, G. Xu, Z. Marcinow, P. W. Rabideau, Tetrahedron
2001, 57, 3637-3644.
5. L. M. Tolbert, J. C. Gregory, C. P. Brock, J. Org. Chem. 1985, 50,
548.
1
2
3
4
5
6
7
8
9
6. a) H.-S. Wu, C.-Y. Wu, Tetrahedron 1977, 38, 2493-2496 b) H.-S.
Wu, C.-Y. Wu, J. Org. Chem. 1999, 64, 1576-1584.
7. G. Mehta, R. Vidya, J. Org. Chem., 2001, 66, 6905-6912.
8. E. J. Corey, U. Koelliker, J. Neuffer, J. Am. Chem. Soc. 1971, 93,
1489-1490.
9. B. Ronan, H. B. Kagan, Tetrahedron: Asymmetry 1992, 3, 115-
122.
10. M. G. Woll, J. D. Fisk, P. R. LePlae, S. H. Gellman, J. Am. Chem.
Soc. 2002, 124, 12447-12452.
11. C. Reynaud, M. Giorgi, H. Doucet, M. Santelli, Tetrahedron Lett.
2009, 50, 3385-3387.
12. P. Angibeaud, J. Defaye, A. Gadelle, J.-P. Utille, Synthesis 1985,
1985, 1123-1125.
13. R. Guevel, L. A. Paquette, J. Am. Chem. Soc. 1994, 116, 1776-
1784.
14. T. E. Nalesnik, J. G. Fish, S. W. Horgan, M. Orchin, J. Org.
Chem. 1981, 46, 1987-1990.
15. F. E. Ziegler, M. Y. Berlin, K. Lee, A. R. Looker, Org. Lett. 2000,
2, 3619-3621.
16. D. Laurenti, M. Feuerstein, G. Pèpe, H. Doucet, M. Santelli, J.
Org. Chem. 2001, 66, 1633-1637.
17. C. Reynaud, Y. Fall, M. Feuerstein, H. Doucet, M. Santelli,
Tetrahedron 2009, 65, 7440-7448.
18. D. S. Connor, G. W. Klein, G. N. Taylor, R. K. Boeckman, J. B.
Medwid, Org. Synth. Coll. Vol. 1988, 6, p.101; 1972, 52, 16 .
19. G. V. B. Madhavan, J. C. Martin, J. Org. Chem. 1986, 51, 1287-
1293.
20. A. J. M. Duisenberg, Utrecht University, The Netherlands
(Utrecht), 1998.
21. M. C. Burla, R. Caliandro, M. Camalli, B. Carrozzini, G. L.
Cascarano, L. de Caro, C. Giacovazzo, G. Polidori, R. Spagna, J.
Appl. Cryst. 2005, 38, 381-388.
22. L. J. Farrugia, J. Appl. Cryst. 1999, 32, 837-838.
23. G. M. Sheldrick, Acta Cryst. 2008, A64, 112-122.
24. Bruker, Madison, Wisconsin, USA 2001.
25. G. M. Sheldrick, University of Göttingen, Germany 1996.
4.9. 1,2,3,4-tetra(hydroxymethyl)-5-
((phenylmethoxy)methyl)cyclopentane (11)
10
11
12
13
14
15
16
451 mg of 10 (1.29 mmol) were dissolved in a mixture of
THF (5.5 mL) and water (0.3 mL). Then 258 mg of Amberlite
IR-120 were added to the mixture which was refluxed for 3.5 h.
After cooling to RT, the mixture was filtered and concentrated
under vacuum. To remove traces of water, toluene (3 mL) was
then added, and the solution was concentrated under vacuum. 11
was obtained as a colorless oil used as such for the next step
1
17 (yield = 90 %). H NMR (400 MHz, CD2Cl2: δ = 7.33 (m, 5H,
Ha), 4.73 (br, OH, 2H), 4.47 (s, 2H, Hb), 4.17 (br, OH, 2H), 3,71
(br, 4H), 3.64 (br, 4H), 3,56 (d, J= 7Hz, 2H), 2,5 (m, 1H), 2,44
(m, 4H). 13C NMR (100 MHz, CD2Cl2): δ = 138.1 (Cqaro), 128.8
(CHaro), 128.2 (CHaro), 128.2 (CHaro), 73.7 (CH2), 69.5 (CH2),
60.8 (CH2-O), 60.7 (CH2-O), 46.1 (CH), 46.0 (CH), 43.1 (CH),
29.4 (CH3). HRMS (DCI CH4): calcd. For C17H27O5 [M+H]+:
311.1858; found: 311.1851.
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4.10. Cis, cis, cis, cis-1,2,3,4,5-
pentakis(hydroxymethyl)cyclopentane (1)
To a solution of 11 (476 mg, 1.53 mmol) in methanol (10
mL) was added 83 mg of 10% Pd/C. The mixture was
hydrogenolyzed under a pressure (1.5 bar) of hydrogen during
3.5 h. The suspension was then filtered over celite, and the
precipitate was washed several times with methanol. After
evaporation of the solvent, 1 was obtained as a colorless oil
1
(yield = 90%). H NMR (300 MHz, MeOD): δ = 3.65 (m, 10H),
2.49 (m, 5H). 13C NMR (75 MHz, MeOD): δ = 61.2 (CH2), 46.7
(CH). MS (NH3): calcd. for C10H21O5 [M+H]+ 221.14; found:
221.1.
Supplementary Material
Copies of the 1H NMR and 13C NMR spectra.
Acknowledgments
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Support by the ICT-FET European Union Integrated Project
AtMol is gratefully acknowledged.