Hydroboration-oxidation of (±)-(1α,3α,3aβ,6aβ) -1,2,3,3a,4,6a-hexahydro-1,3-pentalenedimethanol and its O-protected derivatives: Synthesis of new compounds useful for obtaining (iso)carbacyclin analogues and X-ray analysis of the products

Article abstract of DOI:10.3390/molecules22122032

Hydroboration-oxidation of 2α,4α-dimethanol-1β,5β-bicyclo[3.3.0]oct-6-en dibenzoate (1) gave alcohols 2 (symmetric) and 3 (unsymmetric) in ~60% yield, together with the monobenzoate diol 4a (37%), resulting from the reduction of the closer benzoate by the

Full text of DOI:10.3390/molecules22122032

molecules
Article
Hydroboration-Oxidation of (±)-(1α,3α,3aβ,6aβ)
-1,2,3,3a,4,6a-Hexahydro-1,3-pentalenedimethanol and
Its O-Protected Derivatives: Synthesis of New
Compounds Useful for Obtaining (iso)Carbacyclin
Analogues and X-ray Analysis of the Products
Constantin I. Tănase 1,
Sergiu Shova 3
*
ID , Florea G. Cocu 1, Miron Teodor Căproiu 2, Constantin Drăghici 2 and
1
National Institute for Chemical-Pharmaceutical Research and Development, Department of bioactive
substances and pharmaceutical technologies, 112 Vitan Av., 031299, Bucharest-3, Romania;
fgcocu@gmail.com
Organic Chemistry Center “C.D.Nenitescu”, Spectroscopy Laboratory, 202 B Splaiul Independentei,
060023 Bucharest, Romania; dorucaproiu@gmail.com (M.T.C.); cst_drag@yahoo.com (C.D.)
Institute of Macromolecular Chemistry “Petru Poni”, Crystallography Department, 700478 Iasi, Romania;
shova@icmpp.ro
2
3
*
Correspondence: cvtanase@gmail.com; Tel.: +40-21-321-2117; Fax: +40-21-322-2917
Received: 22 October 2017; Accepted: 16 November 2017; Published: 24 November 2017
Abstract: Hydroboration-oxidation of 2
) gave alcohols (symmetric) and (unsymmetric) in ~60% yield, together with the monobenzoate
diol 4a (37%), resulting from the reduction of the closer benzoate by the intermediate alkylborane.
The corresponding alkene and dialdehyde gave only the triols and in ~1:1 ratio. By increasing the
reaction time and the temperature, the isomerization of alkylboranes favours the un-symmetrical
triol . The PDC oxidation of the alcohols gave cleanly the corresponding ketones and and the
deprotection of the benzoate groups gave the symmetrical ketone 14, and the cyclic hemiketal 15
all in high yields. The ethylene ketals of the symmetrical ketones 11 and 13 were also obtained.
The compounds 11 13 14 could be used for synthesis of new (iso)carbacyclin analogues.
α,4α-dimethanol-1β,5β-bicyclo[3.3.0]oct-6-en dibenzoate
(1
2
3
8
9
9
5
6
,
5
,
6,
,
,
The structure of the compounds was established by NMR spectroscopy and confirmed by
X-ray crystallography.
Keywords:
hydroboration-oxidation;
borane;
sodium
acetoxyborohydride;
hexahydro-1,3-pentalenedimethanol; octahydropentalene-triols; octahydropentalene-ketones;
X-ray analysis
1. Introduction
The synthesis of hydrogenated pentalene ketone intermediates has found applications in obtaining
new drugs, of which the best known are carbacyclin [
and a few antibacterial [10] and antitumor natural products [11
the standard key intermediate has a symmetric ketone for linking the
E-olefination (at the -side chain) and a R group which finally is transformed into an aldehyde used to
introduce the -side chain by a stereoselective Wardworth-Emmons E-olefination with a phosphonate
(Figure 1) [13–16].
In the synthesis of isocarbacyclin analogues, a few pentalene intermediates with different
structures have been used to build the -side chain (Figure 1). The type II intermediate contains
1
] and isocarbacyclin [
12]. In carbacyclin synthesis,
-side chain by a Wittig
2–8] analogues, cioctol [9]
,
I
α
ω
ω
α
Molecules 2017, 22, 2032; doi:10.3390/molecules22122032
www.mdpi.com/journal/molecules

Molecules 2017, 22, 2032
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an exocyclic allylic aldehyde for building the
an allylic alcohol or ester for introducing the
α
-side chain [17], while the type III intermediate has
α
-side chain by a regioselective SN2’ alkylation with
zinc-copper organic reagents [18–20], and the unsymmetric ketone intermediate of type IV links the
α-side chain by different methods [21–24].
The synthesis of new carbacyclin and isocarbacyclin analogs requires new key intermediate
octahydropentalene ketones. In this paper, we describe the synthesis of the ketone-octahydropentalenes
of types V and VI useful for obtaining new carbacyclin and isocarbacyclin analogues.
α-Side chain
O
Steps
α-Side chain
COOH
CHO
COOH
O
O
R'O
R'
R'
R
Steps
Steps
V
ω-Side chain
ω-Side chain
O
R
R
R
R
OH
OH
OH
OH
OH
OH
OH
OH
II
IV
I
III
Isoarbacyclin
and analogues
Carbacyclin
and analogues
Steps
R
VI
Figure 1. Key intermediates for synthesis of carbacyclin and isocarbacyclin analogues.
2. Results and Discussion
Retrosynthetic analysis of the key intermediates
5 and 6 (Scheme 1), indicates that these
compounds could be obtained by a sequence of two reactions: hydration of the double bond of alkene
to an alcohol, followed by the oxidation of the alcohol to the corresponding ketone. The starting
compounds were previously synthesized [25] and have already been used for the synthesis of
“pseudocarbacyclin” type compounds [26 27], of the corresponding diols by hydroxylation with
KMnO4 [28], of the corresponding and -epoxides, by epoxidation of the double bond with
MPBA [29], and of pentalenofuranic compounds by regioselective reactions [30]. Following our
1
1
,
α
β
retrosynthetic analysis, we decided to hydrate the double bond of alkene
with sodium acetoxyborohydride and with borane.
1
by hydroboration-oxidation
CH2OR
CH2OR
8
CH2OR
CH2OR
1
3
1
3
6
1).
6a
3a
5
2
OH
+
+
4
4
OH
OH
7
CH2OR
7
CH2OH
CH2OR
CH2OR
3
4
1
2
a). R = Bz
b). R = Ac
2).
2).
CH2OR
CH2OR
O
O
CH2OR
CH2OR
5
6
Scheme 1. Hydroboration-oxidation of the compounds
1 for obtaining the octahydro-pentalenofurane
ketones
5
and
6
. Reagents and Conditions: (1) (a) Sodium acetoxyborohydride or BH3
·
THF, r.t, 24 h;
◦
(b) 30% H2O2/3 M AcONa or 3 M NaOH, 5 C, ~35 min. (2) PDC/molecular sieves, r.t., overnight.

Molecules 2017, 22, 2032
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Hydroboration-oxidation of alkene 1a with sodium acetoxyborohydride [31] resulted in the
formation, in a non-regioselective manner, of both alcohols 2a (34%) and 3a (25%), slightly in favor
of the symmetrical alcohol
quantity (38%) (Scheme 1). Browsing the literature, we found that in the case of the unsaturated
esters , by forming a cyclic intermediate with 5 or 6 atoms VII, hydroboration of the double bond
proceeded with concomitant reduction of the ester group (Scheme 2) [32].
2. In the reaction, the monobenzoate-triol 4a was also formed in a great
V
CH2 (CH2)n CO OEt
CH2
VI
CH (CH2)n CO OEt
CH2
+ BH3
H2B
V
CH2OOCC6H5
CH2 CH2
CH
HB
(CH2)n
H
O
CH
BH
CH2OC
O
OEt
VII
C6H5
VIII
Scheme 2. Hydroboration mechanism through a cyclic borane ester.
Probably it is the same formation of a similar cyclic ester VIII in the hydroboration of diester
compound , which favored the reduction of the closer ester group to double bond, this reduction
1
being responsible for the formation of the monoacylated triols 4a and 4b.
In the hydroboration-oxidation of diacetate 1b, the monoacetate-triol 4b was formed also in
38% yield, and this is consistent with the mechanism presented in Figure 2 for the formation of
monoesters 4; the corresponding alcohols 2b and 3b were formed in about 1:1 ratio, but their isolation
in pure form by low-pressure chromatography (LPC) was more difficult than in the case of the benzoate
compounds 2a and 2b.
The hydroboration of
followed by H2O2 oxidation gave alcohols 2a
1
with BH3
·
THF, obtained in situ from NaBH4 and dimethyl sulfate,
3a and 4a in 31.5%, 28.8% and 34.5% yield; hence, there is
,
no significant difference in the yields and the ratio of the alcohols between the hydroboration with
NaBH3OOCCH3 and BH3. It is worth mentioning that the isolation of the alcohols by PC is easier for
the benzoate esters than the acetate esters. The formation of the unwanted secondary by-products
4a and 4b could represent also an advantage, because it is easy to selectively protect the primary
hydroxyl group, with a group different from benzoate, like an ether, trityl, tert-butyldimethylsilyl
or other bulky silyl-protecting group, by the methods known in the art, and thus to obtain different
protection of the hydroxymethyl groups, useful for the next steps.
The fact that by-product
the hydroboration-oxidation of benzoate 1a gave the C4-alcohol in a total yield of 62–63%.
We then used the hydroboration-oxidation on the diol (Scheme 3). We observed that
hydroboration with borane is still a slow reaction and a certain amount of alkene remains unreacted.
We used different molar ratios of BH3 THF/ , from 1.2:1 to 4:1, and the results are presented in Table 1.
4 has the hydroxyl group linked at the C4 atom (see below) means that
7
7
·
7
Table 1. Hydroboration of the alkene-diol 7 with borane.
Yield (%)
9
Molar Ratio 7/BH3·THF
Reaction Time (h)
Molar Ratio 8/9
8
8 + 9
1:1.2
1:2.0
1:3.0
1:4.0
7
7
6
6
1.0:1.2
1.0:1.6
1.0:1.05
1.0:1.07
13.3
15.8
31.4
36.7
16.00
25.0
33.1
38.6
29.3
40.8
64.5
73.3

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NaBH4
CH2OH
BH3 THF
8
CHO
CHO
CH2OH
CH2OH
H2O2/3M NaOH
BH3 THF
1
6
1
6a
3a
2
5
OH
+
5
3a
3
4
3
H2O2 /
3M NaOH
4
-
+
CH3CO2BH3Na
OH
7CH2OH
7 CH2OH
CH2OH
H2O2/3M NaOH
10
7
8
9
Scheme 3. Hydroboration-oxidation of alkene-diol
dialdehyde 10 with borane.
7 with borane and sodium acetoxyborohydride and
At a ratio of 2:1 BH3
alcoxyborane groups. The alkoxyborane group, closer to the double bond, hydroborated at the
nearest carbon atom (C-4) with the formation in excess of the un-symmetrical alcohol , through an
intermediate of type VIII (Scheme 2); the yield of alcohols and was still low (40.8%). By increasing
the ratio of BH3 THF/ to 3:1 and 4:1, there remained free borane which increased the yield of alcohols
·
THF/7, the borane reacted with the hydroxymethyl groups forming two
9
8
9
·
7
to 64.4%, and respectively to 73.3%, but there was no selectivity against
9 and the ratio of alcohols was
nearly 1:1 (8/9).
Finally, we performed the hydroboration-oxidation of the double bond, concomitant with the
reduction of the aldehyde groups of dialdehyde 10 (from which we previously [25] obtained the
alkene-diol
(20 h), and a mixture of alkene
hydroboration was done with a greater molar ratio BH3
alkene ) and time was increased to 72 h, the ratio of alcohols (
was performed for 24 h at r.t. and for 2 h at 45–50 ◦C and the ratio of the alcohols changed to ~1.0:2.2
). These suggest that an isomerization of the alkyl-boranes took place from type IX to Xa or Xb
(Scheme 4), more thermodinamically stable in the reaction conditions.
7
by NaBH4 reduction of the aldehyde groups) with 2.2 molar equivalents of BH3
, alcohols and was obtained in a ratio of 1.0:1.1:1.2. When the
THF: of 3:1 (preparative scale on 0.359 M
) was 1.0:1.2. Then another reaction
·
THF
7
9
8
·
7
8/9
7
(8/9
CH2O BH2
CH2O BH2
CH2O BH2
B
B
CH2O BH2
CH2O BH2
CH2O B
H
IX
Xa
Xb
Scheme 4. Isomerization of alkyl-boranes IX to X.
Such isomerizations between alkyl-boranes are known in the literature [33
-configuration of the hydroxyl groups introduced is not important, because the OH is oxidized
in the next step to a ketone. Nonetheless, we believe that the secondary hydroxyl group is mainly
introduced in a orientation, because the access of the hydroboration reagent to the double bond
ocurrs from the exo-side (the bulky crystallized compounds were only analyzed; the compound(s)
remaining in the mother liquors were not analyzed for
isomers). The H5 appears in 1H-NMR as
a broad singlet and is not a clear evidence for the -configuration, but the X-ray diffraction analysis
(Figure 2) of the crystallized triol confirmed the exo-configuration of the secondary alcohol linked
–37]. The α- or
β
β
α/β
α
8

Molecules 2017, 22, 2032
5 of 18
to the C5 position, 5β-OH. Bond distances and angles for compound
8
are listed in Table S1 and
crystallographic data, details of data collection and structure refinement parameters in Table S2
(also for compounds 3, 5 and 14, Supplementary Material).
Figure 2. X-ray molecular structure of the symmetrical triol compound
8 with thermal ellipsoids at
50% probability level. Proposed atom numbering is shown in the scheme attached and will be kept the
same for all compounds.
The compound
8 exhibits a molecular crystal structure where the neutral molecules interact
through O-H···O hydrogen bonding to form a three-dimensional supramolecular network, as shown
in Figure 3. H-bonding parameters are listed in Table 2.
Figure 3. Three-dimensional supramolecular architecture in the crystal structure 8.

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Table 2. H-bond parameters for compound 8.
Distance, Å
Angle D-H···A, deg
Symmetry Code
D-H···A
D-H
H···A D···A
O1–H···O3
O2–H···O1
O3–H···O2
0.82
0.82
0.82
1.90
1.93
1.90
2.701(2)
2.729(2)
2.674(2)
163.9
170.9
156.8
−0.5 − x, y, 0.5 + z
1
−
x,
−
1
−
y,
−
0.5 + z
0.5 + x, −1.5 − y, z
The configuration of the 4-OH in
an oil. For confirming the structure of the unsymmetrical alcohols (OH linked to C4), we synthesized
the tri-benzoates of and (and also of ) to obtain suitable crystals for X-ray analysis, and their
preparation is presented in the paper; their characterization by NMR was also done. At least for the
fractions used for the analysis of the trisbenzoate obtained from , X-ray crystallography confirmed
that the secondary 4-OH group are linked exo ( ) to the carbon atom, as in the case of . The result of
9 was not studied, since the compound was obtained as
3
4
2
3
β
8
single crystal X-ray diffraction study for this compound is shown in Figure 4, while bond distances
and angles are summarized in Table S1.
Figure 4. X-ray molecular structure of non-symmetrical triol tribenzoate compound
3 with atom
labeling scheme and thermal ellipsoids at 50% probability level.
Thus, the hydroboration-oxidation of alcohol
about 38% yield, but by increasing the reaction time and using hydroboration at elevated temperatures,
the unsymmetrical alcohol is formed in excess due to isomerization of the intermediary alkylboranes.
The regioisomers (oil) were separated by LPC; their use in
(crystallized, m.p. 98–99 ◦C) and
the next steps requires the selective protection of the primary hydroxyl groups, as exemplified for the
7 or dialdehyde 10 gives the symmetrical alcohol 8 in
9
8
9
obtaining of 2c (R = Tr) by treating
2a (Scheme 5).
8 with trityl chloride; the following sequence is similar to the one of
The secondary alcohols of
and then the benzoate protecting groups were cleanly removed by transesterification with MeONa in
MeOH (Scheme 5). The structure of ketone is easily established by NMR, just like the structure of the
symmetrical alcohols and , and that of the following compounds obtained from it: the ketone 14
and the ethylene ketal compounds 11 and 13. The X-ray diffraction investigation has confirmed that
compound crystalizes in P21/n space group of monoclinic system and its molecular crystal consists
2 and 3 were oxidized with PDC to the corresponding ketones 5 and 6
5
2
8
5

Molecules 2017, 22, 2032
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of isolated neutral molecules, as illustrated in Figure 5. Bond distances and angles are summarized in
Table S1.
CH2OH
CH2OR
CH2OR
8
CH2OR
CH2OH
CH2OH
TsOH
MeONa/
MeOH
O
O
1
3
6
PDC
6a
3a
5
O
2
OH
4
O
O
CH2OR
CH2OR
7
CH2OR
CH2OH
5
11
CH2OH
a). R = Bz
c). R = Tr
13
2
MeONa/MeOH
MeONa/MeOH
CH2OR
O
CH2OH
CH2OH
TsOH
CH2OR
CH2OR
CH2OH
CH2OH
1
14
PDC
3
4
O
OH
O
OH
7
CH2OR
CH2ORO
CH2OR
CH2O
6
12
15
3 a). R = Bz
Scheme 5. Synthesis of carbonyl compounds from alcohols 2 and 3.
Figure 5. X-ray molecular structure of symmetric ketone bis-benzoate compound
5 with atom labeling
scheme and thermal ellipsoids at 50% probability level.
The structure of ketone
(MeONa/MeOH), the benzoate groups were removed and the symmetrical ketone bis-hydroxymethyl
compound 14 was obtained from ketone . In the case of the unsymmetrical ketone , during the
6 was also established by NMR spectroscopy. By transesterification
5
6
transesterification of the benzoate groups, the closer hydroxymethyl reacted with the ketone C4=O and
gave a cyclic hemiketal 15. Its molecular structure was also confirmed by X-ray crystallography
(Figure 6), showing the formation of the tetrahydrofuran ring with exo-linked 4-hydroxyl of
the hemiketal. According to X-ray crystallography, compound 15 crystallizes in P21/n space group
of monoclinic system with two crystallographically independent but chemically identical units,
denoted as molecules A and B. In Figure 6 only the structure of molecule B is shown.
The crystal packing shows a parallel arrangement of two-dimensional supramolecular layers
extended in the 101 plane. A partial view of the crystal structure is shown in Figure 7. Each layer
involves both independent molecules
A
and
B
connected by O-H···O hydrogen bonds, the formation

Molecules 2017, 22, 2032
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of which is completely realized in the crystal. The corresponding hydrogen bond parameters are listed
in Table 3.
Figure 6. X-ray molecular structure of the un-symmetrical ketone, as internal hemiketal compound 15
(molecule B). Thermal ellipsoids are drawn at 50% probability level.
Figure 7. A fragment of the crystal structure of compound 15 viewed along the b crystallographic axis.

Molecules 2017, 22, 2032
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Table 3. H-bond parameters for compound 15.
Distance, Å
Angle D-H···A, deg
Symmetry Code
D–H···A
D-H
H···A D···A
O2A–H···O1B
O3A–H···O3B
O2B–H···O2A
O2B–H···O3A
0.82
0.82
0.82
0.82
1.94
2.01
1.96
1.94
2.754(2)
2.794(2)
2.781(2)
2.757(2)
171.8
160.8
173.8
171.4
1 − x, 1 − z
0.5 − x, 0.5 + y, 1.5 − z
−1 − x, 1 − y, 1 − z
−1 + x, y, z
Both ketone groups of compounds
5 and 6 were transformed into the corresponding ethylene
ketals by standard treatment with ethylene glycol (in C6H6 at reflux, TsOH catalyst). In the first case,
we obtained compound 11 which by a similar transesterification reaction, gave compound 13, with the
ketone protected as an ethylene ketal, a group useful for the next reactions for discrimination between
the two hydroxymethyl groups. In the case of compound 12, though the reaction proceeded until all
6
6
reacted (TLC), during work-up or column chromatography purification, only the starting compound
was isolated, indicating that slightly acid conditions favored the deprotection of the ethylene
ketal group. The applications of the symmetric-ketone compounds in the synthesis of new carbacyclin
analogues are in progress.
3. Materials and Methods
3.1. General Information
Melting points (uncorrected) were determined in open capillaries on an OptiMelt
apparatus (MPA 100, Stanford Research System, Inc., Sunnyvale, CA, USA). The progress of
the reactions was monitored by TLC on silica gel 60F254 plates (Merck, Darmstadt, Germany)
in solvent systems:
I
(benzene–ethyl acetate–hexane, 5:3:2), II (cyclohexane–ethyl acetate, 5:1),
(hexane–ethyl
III (ethyl acetate–methanol–acetic acid, 90:13:1), IV (acetone–hexanes, 2:1),
V
acetate–acetic acid, 5:3:0.1), VI (hexane–ethyl acetate–acetic acid, 5:3:0.1), VII (ethyl
acetate–hexane–acetic acid, 5:1:0.1). Spots were visualized in UV or with 15% H2SO4 in MeOH
◦
(heating at 110 C, 10 min) and 2,4-dinitrophenylhydrazine reagent for ketones. The compounds were
purified by low pressure chromatography (<2 atm) (LPC), on a glass column, in the solvent systems
presented at experimental. IR spectra were recorded on an FT-IR spectrometer 100 (Perkin Elmer,
Shelton, CT, USA) and frequencies are expressed in cm−1. MS were recorded on a 1200 L/MS/MS
triple-quadrupole instrument (Varian, Inc., Walnut Creek, CA, USA) equipped with an ESI interface,
fragments obtained by collision with Ar and relative abundances (%) are given in parenthesis.
1H-NMR and 13C-NMR spectra were recorded on a Varian Gemini 300 BB spectrometer (300 MHz for
1H and 75 MHz for 13C, Varian, Inc., Palo Alto, CA, USA). Chemical shifts are given in ppm relative to
TMS as an internal standard. Complementary spectra: 2D-NMR and decoupling were done for correct
assignment of NMR signals. The numbering of the carbon atoms in the compounds is presented in
the Schemes.
Crystallographic measurements were carried out with an XCALIBUR E CCD diffractometer
(Oxford-Diffraction, Ltd., Abingdon, Oxfordshire, UK) equipped with graphite-monochromated
Mo-K
α radiation. Single crystals were positioned at 40 mm from the detector and 481, 258,
251, and 774 frames were measured each for 20, 10, 5, and 20 s over 1◦ scan width for
8, 3, 5
and 15, respectively. The unit cell determination and data integration were carried out using
the CrysAlis package of Oxford Diffraction [38]. The structures were solved by direct methods
using the Olex2 [39] software (OlexSys Ltd., Durham University, UK) with the SHELXS structure
solution program and refined by full-matrix least-squares method on F2 with SHELXL-97 [40].
The atomic displacements for the non-hydrogen atoms were refined using an anisotropic model.
Hydrogen atoms were placed in fixed, idealized positions and refined as rigidly bonded to the
corresponding atoms. Positional parameters of the H attached to the O atoms were obtained

Molecules 2017, 22, 2032
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from difference Fourier syntheses and verified by the geometric parameters of the corresponding
hydrogen bonds. In the absence of significant anomalous scattering, the absolute configuration for
could not be reliably determined. Friedel pairs were merged and any references to the Flack parameter
were removed. The molecular plots were obtained using the Olex2 program. CCDC: 1566141 (for ),
1566142 (for ), 1566143 (for ) and 1566145 (for 15). These data can be obtained free of charge via
8
8
3
5
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.ca.ac.uk).
3.2. Hydroboration of 2α,4α-Dimethanol-1β,5β-bicyclo[3.3.0]oct-6-en dibenzoate with Sodium
Acetoxy-Borohydride
To a suspension of 98% NaBH4 (772 mg, 20 mmol) in anhydrous THF (60 mL), cooled on an
ice-water bath, 1.14 mL (1.2 g, 20 mmol) 99.9% acetic acid were added in Ar atmosphere, under stirring
for 10 min. and stirring was continued for 20 min. A solution of 1a (7.53 g, 20 mmol) in THF
(15 mL) was added during 20 min, stirring was continued overnight, monitoring the reaction by TLC
(I, Rf1b = 0.91, Rf3a = 0.47, Rf2a = 0.35, Rf4a = 0.05). Water (5 mL) was added, the reaction mixture was
cooled on an ice-water bath, then the alkylboranes were oxidized with 30% H2O2 (6 mL) and 3 M
sodium acetate (10 mL) (instead of 3 M NaOH to prevent the hydrolysis of the benzoate protecting
groups) both added at the same time during ~15 min, and stirred for 20 min. Ethyl ether (50 mL) was
added, phases were separated, aqueous phase was extracted with ether (3
×
50 mL), organic phases
were washed with sat. soln. NaHCO3 (50 mL), dried (MgSO4) and concentrated, obtaining 7.77 of
crude product, which was purified by low-pressure chromatography (LPC) (eluent: hexanes, then
solvent system: benzene–hexane–ethyl acetate, 5:3:2). The following fractions were eluted:
(a) 1.6 g (21.2%) of unreacted 1a, (the yields below are based on the reacted 1a).
(b) 1.54
g
(24.8%, based on the reacted alkene) of pure unsymmetrical alcohol
,3a ,6a )-1,2,3,3a,4,5,6,6a-octahydro-4-hydroxy-1,3-diyl)bis(methylene) dibenzoate
3a) as an oil, IR (2% CHCl3): 3550–3400, 3350, 3035, 2910–2885, 2850, 1695, 1595, 1580, 1440,
ppm, J Hz): 7.98 (dd, 2H, 8.0,
(
(
±
)-(1
α
,3
α
β
β
1350, 1270–1200, 1090, 1055, 1040, 945 cm−1, 1H-NMR (DMSO-d6,
δ
1.2, H-o), 7.95 (dd, 2H, 8.0, 1.2, H-o), 7.67–7.61 (m, 2H, 8.0, 1.2, H-p), 7.51 (apparent t, 2H, 8.0,
H-m), 7.50 (t, 2H, 8.0, H-m), 4.60 (d, 1H, OH, exchangeable with D2O, 4.8), 4.51 (dd,1H, 11.1, 5.0,
H-7), 4.18–4.45 (m, 3H, H-7, H-8), 3.82 (m, 1H, H-4), 2.70 (m, 1H, H-3a), 2.20–2.40 (m, 3H, H-6a,
H-1, H-3), 1.05–1.90 (m, 6H, H-5, H-6, H-2), 13C-NMR (DMSO-d6,
δ ppm): 165.75, 165.58 (COO),
133.19, 133.08 (C-p), 130.04, 129.81 (C-q), 129.12, 129.03 (C-o), 128.71, 128.61 (C-m); 72.98 (C-4),
65.60 (C-7 or C-8), 65.21 (C-8 or C-7), 51.58 (C-3a), 42.61 (C-1), 40.42 (C-3 or C-6a), 40. 40 (C-6a or
C-3), 35.85 (C-5), 31.02 (C-2), 23.01 (C-6), elem. anal. calcd for C24H26O5 (%), C: 73.07, H: 6.64,
found: C: 72.80, H: 6.42.
(c) 2.11 g (34%) of pure symmetrical more polar alcohol, ( )-(1α,3α,3aβ,6aβ)-1,2,3,3a,4,5,6,6a-5-
±
hydroxyoctahydropentalene-1,3-diyl)bis(methylene) dibenzoate (2a) which was crystallized
(1.69 g) by ethyl acetate-gas extraction, m.p. 115–117 ◦C. A fraction recrystallized twice had m.p.
119.5–120.5 ◦C, 1H-NMR (CDCl3,
δ ppm, J Hz): 8.03 (dd, 4H, 7.1, 1.4, H-o), 7.56 (tt, 2H, 7.1, 1.4,
H-p), 7.44 (t, 4H, 7.1, H-m), 4.41 (dd, 2H, 11.0, 7.1, H-7, H-8), 4.31 (dd, 2H, 11.0, 8.2, H-7, H-8),
4.11 (tt, 1H, 5.9, 10.4, H-5), 2.69–2.64 (m, 2H, H-3a, H-6a), 2.48–2.38 (m, 2H, 8.2, 7.1, H-1, H-3),
2.05–1.97 (m, 2H, 10.4, 5.9, H-4, H-6), 1.89 (dt, 1H, 11.1, 5.4, H-2), 1.34 (q, 1H, 11.1, H-2), 1.36–1.26
(m, 2H, 10.4, 5.9, H-4, H-6), 13C-NMR (CDCl3,
δ ppm): 166.45 (COO), 132.88 (2C-p), 130.24 (2C-q),
129.48 (4C-o), 128.32 (4C-m), 73.33 (C5), 65.58 (C-7, C-8), 41.05 (C-1, C-3 or C-3a, C-6a), 40.85 (C-3a,
C-6a or C-1, C-3), 35.98 (C-4, C-6), 30.01 (C-2), elem. anal. Calcd. for C24H26O5, C:d 73.07, H: 6.64,
found: C: 72.88, H: 6.52.
(d) 1.72
-octahydropentalen-1-yl)methyl benzoate (4a), which was crystallized by ethyl acetate-gas
extraction to give 1.12 g of product, m.p. 74–77 ◦C, 1H-NMR (CDCl3,
ppm, J Hz): 8.02 (dd, 2H,
1.4, 7.4, H-o), 7.53 (t, 1H, 1.4, 7.4, H-p), 7.44 (t, 2H, 7.4, 2H-m), 4.36 (dd, 1H, 7.1, 11.0, H-8),
g
(37.6%) pure
(
±
)-(1α,3α,3aβ,6aβ)-1,2,3,3a,4,5,6,6a-4-hydroxy-3-(hydroxymethyl)
δ

Molecules 2017, 22, 2032
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4.27 (dd, 1H, 8.0, 11.0, H-8), 4.02 (ddd, 1H, 5.5, 8.2, 10.4, H-4), 3.85 (dd, 1H, 5.8, 11.0, H-7),
3.76 (t, 1H, 11.0, H-7), 3.14–3.00 (br d, 2H, OH), 2.86 (qv, 1H, 9.9, H-6a), 2.51 (dt, 1H, 8.2, 9.9,
H-3a), 2.44–2.28 (m, 2H, H-1, H-3), 1.98 (dt, 1H, 5.5, 11.0, H-5), 1.75 (m, 1H, H-6), 1.67 (dt, 1H,
5.5, 12.6, H-2), 1.47 (dd, 1H, 5.8, 11.0, H-5), 1.27 (m, 1H, H-6), 0.99 (q, 1H, 12.6, H-2), 13C-NMR
(CDCl3, δ ppm): 166.68 (COO), 133.06 (C-p), 130.45 (C-q), 129.65 (C-o), 128.51 (C-m), 73.99 (C-4),
65.56 (C-8), 63.50 (C-7), 52.09 (C-3a), 43.68 (C-1), 42.98 (C-6a), 41.11 (C-3), 35.10 (C-5), 30.43 (C-2),
23.76 (C-6).
3.3. Hydroboration of 2α,4α-Dimethanol-1β,5β-bicyclo[3.3.0]oct-6-en diacetate with Sodium
Acetoxy-Borohydride
Hydroboration of diacetate 1b (20 mmol) was realized as for 1a, affording 5.23 g
of crude product which was similarly purified.
The following fractions were collected:
0.86 g (3.41 mmol) of starting alkene 1b, (16.9%); 0.13 g slightly impure unsymmetrical
alcohol 3b, as an oil; 1.62 g of a mixture of alcohols 2b and 3b, as an oil; 0.26 g
of slightly impure symmetric alcohol 2b
)-(1 ,3 ,3a ,6a )-1,2,3,3a,4,5,6,6a-4-hydroxy-3-(hydroxymethyl)octahydro-pentalen-1-yl)methyl
acetate (4b) which gave 1.32 g (28.8%) as of the title product as needles, m.p. 58–59.5 ◦C,
upon crystallization from ethyl acetate-hexane; 1H-NMR (DMSO-d6,
ppm, J Hz): 3.97 (d, 2H, 7.7,
, as an oil and 1.74 g (7.6 mmol, 38%) of
(
±
α
α
β
β
δ
H-8), 3.77 (dd + TFA, 1H, 3.3, 6.3, H-4), 3.62 (dd, 1H, 7.6, 10.8, H-7), 3.54–3.40 (br, 2H, OH), 3.45 (dd,
1H, 7.4, 10.8, H-7), 2.57 (dt + TFA, 1H, 6.2, 9.2, H-6a), 2.20 (dt, 1H, 6.3, 8.8, H-3a), 2.08–1.98 (m, 2H, H-1,
H-3), 1.98 (s, 3H, CH3), 1.68 (m, 1H, H-5), 1.61 (dt, 1H, 6.5, 12.8, H-2), 1.49 (m, 1H, H-6), 1.28 (m, 1H,
H-5), 1.13 (m, 1H, H-6), 0.85 (q, 1H, 12.8, H-2), 13C-NMR (CDCl3,
δ ppm): 170.40 (COO), 72.72 (C-4),
64.69 (C-8), 61.97 (C-7), 51.83 (C-3a), 43.83 (C-1), 42.53 (C-6a), 40.50 (C-3), 35.40 (C-5), 31.03 (C-2), 23.73
(C-6), 20.73 (CH3), elem. anal. calcd. for C12H20O4 (%), C: 63.12, H: 8.83, found: C: 63.20, H: 8.65.
3.4. Hydroboration of ( )-(1α,3α,3aβ,6aβ)-1,2,3,3a,4,6a-Hexahydro-1,3-pentalenodimethanol Dibenzoate with
±
Borane (BH3·THF)
To a suspension of 98% NaBH4 (0.3 g, 7.8 mmol) in anhydrous THF (25 mL), dimethyl sulfate
(DMS, 0.76 mL, 1.014 g, 7.8 mmol) was added dropwise under mechanical stirring under an Ar
atmos◦phere. The reaction mixture was stirred for 2 h at room temperature (r.t.) and for 30 min at
◦
50–60 C, cooled under
−
10 C, and a solution of alkene dibenzoate 1a (7.58 g, 20 mmol; alkene/borane
molar ratio of 2.56:1, for forming the trialkylborane) in THF (15 mL) was added dropwise and stirred
for 20 h at r.t., following the reaction by TLC. An equal quantity of borane was prepared and added to
◦
the reaction mixture at 10–13 C, then stirred overnight at r.t. Though all the alkene was not consumed,
the alkylboranes formed were oxidized, after cooling on an ice-water bath, with 30% H2O2 (4.4 mL)
and 1 N NaOH (8.1 mL), added dropwise at the same time. The stirring was continued then for 20 min
at r.t., 40 mL water were added and the mixture was extracted with dichloromethane (3
×
100 mL).
Organic phases were washed with brine (2 50 mL), dried (MgSO4), concentrated and the crude
×
product (7.2 g) was purified as in ex. 3.2, resulting 1.25 g of unreacted alkene (16.6%), 1.90 g (28.8%) 3a
2.07 g (31.5%) 2a and 1.67 g (34.5%) 4a.
,
3.5. Hydroboration of Alkene-Diol 7 with Sodium Acetoxyborohydride
2α,4α-Dimethanol-1β,5β-bicyclo[3.3.0]octene-6 7 (6.72 g, 40 mmol) dissolved in anhydrous THF
(50 mL), was hydroborated with acetoxyborohydride (as described in Section 3.2), obtained from
◦
NaBH4 (4.63 g, 120 mmol) and 99.9% acetic acid (7.2 mL, 120 mmol) in THF (100 mL) for 3 h at 0–5 C,
and over a weekend at r.t. TLC (III, Rf7 = 0.84, Rf9 = 0.62, Rf8 = 0.41). The alkylborane was oxidized with
30% H2O2 (33 mL) and 3 N NaOH (60 mL) added dropwise in the same time. The solvent was removed
under reduced pressure, the concentrate was co-evaporated with anhydrous ethanol (3
extracted with ethanol, resulting in an 8.9 g of a mixture of triols and . The pure products were
obtained by LPC (silica gel, eluent: acetone–hexanes, 1:2, then 1:1), resulting in 2.57 g (34.5%) of the
×
50 mL),
8
9

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symmetric alcohol
8
as an oil and 3.58 g (48%) of pure unsymmetric alcohol
9
as a slightly yellow oil
(the isolated alcohols were obtained in a 1.0:1.4 ratio of 8/9).
(a) )-(1 ,3 ,3a ,6a
(
±
α
α
β
β
)-1,2,3,3a,4,5,6,6a-5-Hydroxyoctahydropentalene-1,3-diyl)dimethanol
(
8
).
The symmetric alcohol was crystallized from acetone-hexanes giving 1.35 g
8 as needle crystals,
◦
m.p. 98–99 C. IR (KBr): 3380–3180, 2945, 2980, 2850, 1480, 1460, 1440, 1350, 1200, 1080, 1020, 960,
870 cm−1, 1H-NMR (DMSO-d6,
δ ppm, J Hz): 4.26 (t, 2H, 5.0, HO-C7,8, exchangeable with D2O),
4.16 (d, 1H, 3.0, O-C5, exchangeable with D2O), 4.10 (br s, 1H, H-5), 3.34 (dd, 4H, 7.3, 5.0, H-7,
H
H-8), 2.67–2.60 (m, 2H, H-3a, H-6a), 1.99–1.89 (m, 2H, 7.3, 5.5, H-1, H-3), 1.56 (dt, 1H, 12.1, 5.5,
H-2), 1.52–1.44 (m, 2H, H-4, H-6), 1.30–1.20 (m, 2H, H-4, H-6), 0.71 (q, 1H, 12.1, H-2), 13C-NMR
(DMSO-d6, δ ppm): 72.92 (C-5), 61.97 (C-7, C-8), 44.31 (C-1, C-3 or C-3a, C-6a), 41.98 (C-3a, C-6a
or C-1, C-3), 35.30 (C-4, C-6), 30.62 (C-2), MS, m/z: 168 (PM), 150, 137 (68%), 109 (73%), 95, 93, 91,
79 (PB).
(b)
(
±
)-(1
α
,3
α
,3a
β
,6a
β
)-1,2,3,3a,4,5,6,6a-4-Hydroxyoctahydropentalene-1,3-diyl)dimethanol
(9).
1
IR: practically identical to that of
8
, H-NMR (DMSO-d6,
δ
ppm, J Hz): 4.65 (dd, 1H, 3.8, 0.5,
H
H
O-C4, exchangeable with D2O), 4.43 (t, 1H, 5.6, HO-C7, exchangeable with D2O), 4.37 (t, 1H, 4.7,
O-C8, exchangeable with D2O), 3.76 (dt, 1H, 6.7, 7.3, H-4), 3.62 (dd, 1H, 10.7, 7.7, H-7), 3.46 (dd,
1H, 10.7, 7.5, H-7), 3.37 (d, 2H, 6.0, H-8), 2.56 (d, 1H, 9.0, H-6a), 2.20 (q, 1H, 8.8, H-3a), 2.00 (m, 1H,
H-3), 1.90 (m, 1H, H-1), 1.69–1.44 (m, 3H, H-2, H-6, H-5), 1.28 (m, 1H, H-5), 1.17 (m, 1H, H-6), 0.74
(q, 1H, 12.3, H-2), 13C-NMR (DMSO-d6,
δ ppm): 72.61 (C-4), 61.88 (C-7), 61.37 (C-8), 51.71 (C-3a),
44.30 (C-1), 43.62 (C-3), 42.45 (C-6a), 35.24 (C-5), 31.01 (C-2), 22.83 (C-6), MS, m/z: 168 (PM), 150,
138, 119, 106, 93, 91, 83 (PB).
3.6. Hydroboration of Alkene-Diol 7 with Borane
Alkene (3.26 mmol) was hydroborated with borane in the conditions mentioned in Section 3.4
and using the ratios of borane/ mentioned in Table 1. The purification of the crude mixtures was
7
7
performed as in Section 3.5 and the yields are presented in Table 1.
3.7. Hydroboration of Alkene-Dialdehyde 10 with Borane (at a 0.359 M Scale)
To a solution of BH3
dimethyl sulfate (105 mL, 1.056 mol) in THF (500 mL), cooled to <
,4 -diformyl-1 ,5 -bicyclo[3.3.0]octene-6 (0.359 mol, previously co-evaporated with benzene)
in THF (150 mL) was added dropwise in 90 min, maintaining the temperature under
◦C.
The temperature was left to reach the r.t. and the reaction mixture was further stirred over weekend.
TLC (IV, Rf7 = 0.43, Rf9 = 0.23, Rf8 = 0.09). The crude product (75 g) was purified (3 ) by LPC
(acetone–hexanes, 1:1, then 2:1), resulting 7.55 g (12.5%) alkene , 29.77 g (44.5%) as an oil and 25.1 g
(37.5%)
, crystallized in mass, m.p. 102–104 ◦C (twice recrystallized from acetone). The ratio of
·
THF, prepared from 98% NaBH4 (41 g, 1.056 mol) and 97%
−
10 ◦C, a solution of
2
α
α
β β
−
5
×
7
9
8
9/8
was 1.185/1.0.
3.8. Benzoylation of Symmetrical Alcohol 2a
The dibenzoate alcohol 2a (160 mg, 0.4 mmol) in pyridine (5 mL) was benzoylated with
benzoyl chloride (0.24 mL) in usual conditions. TLC (V, Kieselgel plastifollien, Merck, Rf2a = 0.57,
Rf2a-triBz = 0.93). The crude product was purified by LPC, resulting 190 mg (95.2%) of symmetrical
◦
1
tribenzoate 2a, m.p. 85–87 C (crystallized from hexane–ethyl acetate), H-NMR (CDCl3,
δ ppm,
J Hz): 8.05–7.99 (m, 6H, H-o), 7.58–7.53 (m, 3H, H-p), 7.46–7.40 (m, 6H, H-m), 5.57 (t, 1H, 3.3, H-5),
4.43 (dd, 2H, 7.1, 11.0, H-7, H-8), 4.33 (dd, 2H, 8.0, 11.0, H-7, H-8), 3.12–3.03 (m, 2H, H-3a, H-6a),
2.60–2.51 (m, 2H, H-1, H-3), 2.11–2.04 (m, 2H, H-4, H-6), 1.95 (dt, 1H, 5.5, 12.4, H-2), 1.73–1.62 (m, 2H,
H-4, H-6), 1.26 (q, 1H, 12.4, H-2), 13C-NMR (CDCl3,
δ ppm): 166.63 (COO), 133.09, 132.97 (3C-p), 130.24
(3C-q), 129.71, 129.67 (6C-o), 128.53, 128.46 (6C-m), 79.06 (C-5), 65.58 (C-7, C-8), 42.97 (C-1, C-3 or C-3a,
C-6a), 40.99 (C-3a, C-6a or C-1, C-3), 33.52 (C-4, C-6), 30.59 (C-2).

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3.9. Benzoylation of Unsymmetrical Alcohol 3a
The dibenzoate alcohol 3a (160 mg, ◦0.4 mmol) was benzoylated as above; 150 mg (73%) of
un-symmetrical tribenzoate 3a, m.p. 82–83 C (hexane-ethyl acetate) were obtained, 1H-NMR (CDCl3,
δ
ppm, J Hz): 8.05 (dd, 2H, 1.4, 7.8, H-o), 7.94 (dd, 2H, 1.4, 7.8, H-o), 7.87 (dd, 2H, 1.4, 7.4, H-o),
7.57 (tt, 1H, 1.4, 7.8, H-p-in 4-O-Bz), 7.50–7.23 (m, 8H, 2H-p, 6H-m), 5.33 (dt, 1H, 5.5, 8.2, H-4), 4.51 (dd,
1H, 6.9, 11.3, H-7 or H-8), 4.51 (dd, 1H, 8.0, 11.3, H-7 or H-8), 4.43 (dd, 1H, 6.9, 11.0, H-8 or H-7), 4.37
(dd, 1H, 8.0, 11.0, H-8 or H-7), 3.00–2.89 (m, 2H, H-3a, H-6a), 2.59–2.42 (m, 2H, H-1, H-3), 2.23 (ddt,
1H, 3.6, 5.8, 12.1, H-5), 1.95 (dt, 1H, 5.5, 12.6, H-2), 1.87 (m, 1H, H-6), 1.68 (m, 1H, H-5), 1.51 (m, 1H,
H-6), 1.26 (q, 1H, 12.6, H-2), 13C-NMR (CDCl3,
δ ppm): 166.63, 166.45, 166.19 (3COO), 133.11 (C-p),
132.85 (2C-p), 130.45 (2-C-q), 130.24 (C-q), 129.65 (6C-o), 128.55, 128.31, 128.27 (6C-m), 76.58 [C-4, with
Cr(acac)3], 65.49 (C-7 or C-8), 64.94 (C-8 or C-7), 49.67 (C-3a), 43.38 (C-1), 41.09, 40.98 (C-3, C-6a), 33.26
(C-5), 31.43 (C-2), 24.23 (C-6).
3.10. Benzoylation of Monobenzoate Alcohol 4a
The monobenzoate alcohol 4a (145 mg, 0.5 mmol) was benzoylated as above; 230 mg (73%) of
◦
tribenzoate 4a, m.p. 83–85 C (hexane–ethyl acetate); 1H-NMR (CDCl3,
δ ppm, J Hz): 8.05 (dd, 2H, 1.4,
7.4, H-o), 7.94 (dd, 2H, 1.4, 7.4, H-o), 7.87 (dd, 2H, 1.4, 7.4, H-o), 7.57 (tt, 1H, 1.4, 7.8, H-p-in 4-O-Bz),
7.50–7.42 (m, 2H-p), 7.35–7.20 (m, 6H-m), 5.33 (dt, 1H, 5.5, 8.2, H-4), 4.51 (dd, 1H, 6.9, 11.3, H-7 or 8),
4.46 (dd, 1H, 8.0, 11.3, H-7 or H-8), 4.43 (dd, 1H, 6.9, 11.0, H-8 or H-7), 4.37 (dd, 1H, 8.0, 11.0, H-8
or H-7), 3.00–2.88 (m, 2H, H-3a, H-6a), 2.60–2.39 (m, 2H, H-1, H-3), 2.23 (ddt, 1H, 3.5, 5.8, 12.1, H-5),
1.94 (dt, 1H, 5.5, 12.6, H-2), 1.87 (m, 1H, H-6), 1.68 (m, 1H, H-5), 1.51 (m, 1H, H-6), 1.26 (q, 1H, 12.6, H-2),
13C-NMR (CDCl3,
δ ppm): 166.62, 166.43, 166.18 (3COO), 133.10, 132.85, 132.81 (3C-p), 130.445 (2-C-q),
130.25 (C-q), 129.70, 129.65 (6C-o), 128.55, 128.31, 128.27 (6C-m), 76.76, 65.49 (C-7 or C-8), 64.94 (C-8
or C-7), 49.70 (C-3a), 43.38 (C-1), 41.09, 40.99 (C-3, C-6a), 33.27 (C-5), 31.43 (C-2), 24.23 (C-6); mixt.
m.p. tri-Bz-2a + triBz-3a = 69–72 ◦C; mixt. m.p. tri-Bz-2a + triBz-4a = 72–74 ◦C; mixt. m.p. tri-Bz-3a
triBz-4a = 83–85 ◦C.
+
3.11. Tritylation of Symmetric Triol 8
The symmetric triol
7 (3.17 g, 17.02 mmol) was dissolved in pyridine (40 mL) and 97% trityl
chloride (10.2 g, 35.6 mmol) was added in portions over 30 min at r.t. under stirring. Stirring was
continued over weekend (3 days) and TLC (IV, Rf7 = 0.11, Rf2c = 0.53, Rf2c-tris-Tr = 0.80) still showed
the presence of a minor quantity of the starting triol. Another 1 g of trityl chloride was added and
the solution was stirred for 3 h at 45–50 ◦C. The cooled reaction mixture was poured over crushed ice,
stirred for 1 h, the product was extracted with dichloromethane (3
×
100 mL), the unified organic
solutions were washed with sat. soln. NaHCO3 (2 100 mL), brine (100 mL), dried (MgSO4), filtered,
×
concentrated and co-evaporated with toluene. The crude product was crystallized from methanol
and recrystallized from methanol-ethyl acetate, resulting 3.84 g of pure compound 2c, m.p. 98–101 ◦C
[By LPC purification of the concentrated mother liquors (eluent, hexanes–ethyl acetate, 3:1), 6.65 g
(total yield: 92%) of pure compound 2c and 700 mg of almost pure tristrityl derivative (4.5%) were
obtained], IR (KBr): 3600–3300, 3040–3020, 2920–2850, 1585, 1480, 1440, 1150, 1055, 740, 695 cm−1
1H-NMR (CDCl3,
ppm, J Hz): 7.43 (dd, 12H, 1.7, 8.5, H-o), 7.28 (t, 12H, 8.5, H-m), 7.21 (td, 6H, 1.7, 8.5,
,
δ
H-p), 4.21 (br s, 1H, H-5), 3.14 (dd, 2H, 6.5, 8.6, H-7, H-8), 2.96–2.85 (m, 2H, H-3a, H-6a), 2.80 (t, 2H,
8.6, H-7, H-8), 2.42–2.34 (m, 2H, 6.5, H-1, H-3), 1.71 (dt, 1H, 12.2, 5.1, H-2), 1.55–1.44 (m, 2H, 6.5, 13.1,
H-4, H-6), 1.03–0.95 (m, 2H, H-4, H-6), 0,66 (q, 1H, 12.2, H-2), 13C-NMR (CDCl3,
δ ppm): 144.42 (6C-q),
128.70 (12C, C-o), 127.65 (12C, C-m), 126.79 (6C, C-p), 86.22 (2C-q), 75.10 (C-5), 64.26 (2C, C-7, C-8), 42.34
(2C, C-3a, C-6a), 42.14 (2C, C-1, C-3), 35.91 (2C, C-4, C-6), 30.87 (C-2), elem. anal. calcd for C48H46O3:
th. C: 85.93, H: 6.91, found: C: 85.10 (−0.83, due to traces of solvent, not determined), H: 6.79.

Molecules 2017, 22, 2032
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3.12. PDC Oxidation of Alcoholdibenzoate 2a
To alcohol 2a (1.2 g, 2.84 mmol) dissolved in dichloromethane (60 mL), PDC (1.65 g, 4.26 mM) and
molecular sieve (2 g) were added and stirred overnight, monitoring the reaction by TLC (I, Rf2a = 0.40,
Rf5a = 0.66). The reaction mixture was diluted with ethyl ether, filtered of a anh. MgSO4 bed,
the bed was washed with ether, the filtrate was concentrated and the crude product was purified
by LPC (hexanes–ethyl acetate, 3:1 or benzene–ethyl acetate–hexane 5:3:2) and the pure ketone,
(
±
)-(1
α
,3
α
,3a
β
,6a
β
)-1,2,3,3a,4,6a-5-oxooctahydropentalene-1,3-diyl)bis(methylene) dibenzoate (
5
) was
◦
obtained in more than 90% yield as an oil, which crystallized in time, m.p. 79.5–81.5 C (ethyl
ether–hexane), IR (1% in CHCl3): 3030, 2910–1880, 1700–1690, 1595, 1580, 1450, 1250–1200, 1100,
950 cm−1, 1H-NMR (CDCl3,
δ ppm, J Hz): 8.00 (d, 4H, 7.1, H-o), 7.57 (t, 2H, 7.1, H-p), 7.44 (d, 4H, 7.1,
H-m), 4.39 (dd, 2H, 11.4, 6.3, H-7, H-8), 4.30 (dd, 2H, 11.4, 7.6, H-7, H-8), 3.10–3.03 (m, 2H, H-1, H-3),
2.38 (dd, 2H, 18.6, 6.2, H-4, H-6), 2.30 (dd, 2H, 18.6, 6.5, H-4, H-6), 2. 08 (dt, 1H, 12.3, 6.5, H-2),
1.46 (q, 1H, 12.3, H-2), 13C-NMR (CDCl3,
δ ppm): 218.50 (C-5), 166.26 (COO), 133.01 (C-p), 129.87 (C-q),
129.42 (C-o), 128.36 (C-m), 65.25 (2C, C-7, C-8), 41.09 (2C, C-3a, C-6a), 40.29 (2C, C-1, C-3), 38.71 (2C, C-4,
C-6), 30.47 (C-2), elem. anal. calcd. for C24H24O5, C: 73.45, H: 6.16, found: C: 73.49, H: 6.22.
3.13. PDC Oxidation of Alcoholdibenzoate 3a
Dibenzoate alcohol 3a (0.81 g, 2.84 mmol) in dichloromethane (50 mL), was oxidized as
before with PDC (1.20 g, 3.19 mmol) and molecular sieve (1.35 g), overnight. TLC (I, Rf3a = 0.50,
Rf6a = 0.68) showed still the presence of 3a and more PDC (0.35 g) were added and stirring was
continued for 3 days. After work-up and purification as above, 0.67 g (83.3%) of pure ketone,
(
±
)-(1
α
,3
α
,3a
β
,6a
β
)-1,2,3,3a,4,6a-4-oxooctahydropentalene-1,3-diyl)bis(methylen◦e) dibenzoate (
6)
were obtained as an oil, which crystallized overnight in the refrigerator, m.p. 61–63 C, IR (1% CHCl3),
practically the same as those of ketone
1100, 1060, 950 cm−1, 1H-NMR (CDCl3,
5
: 3030, 2910–2880, 1700–1690, 1595, 1580, 1450, 1250–1200,
δ
ppm, J Hz): 8.05 (dd, 2H, 8.3, 1.4, H-o), 7.98 (dd, 2H, 8.3, 1.4,
H-o), 7.58 (tt, 1H, 8.3, 1.4, H-p), 7.55 (tt, 1H, 8.3, 1.4, H-p), 7.45 (t, 2H, 8.3, H-m), 7.43 (t, 2H, 8.3, H-m),
4.55 (dd, 1H, 11.4, 3.6, H-7 or H-8), 4.48 (dd, 1H, 6.9, 11.1, H-8 or H-7), 4.44 (dd, 1H, 11.1, 6.9, H-7 or
H-8), 4.43 (dd, 1H, 11.4, 7.9, H-8 or H-7), 3.01 (m, 1H, H-1), 2.83 (t, 1H, 10.8, H-3a), 2.78 (m, 1H, H-3),
2.65 (m, 1H, H-6a), 2.20–2.28 (m, 2H, H-5), 2.00–2.15 (m, 2H, H-2, H-6), 1.80 (dq, 1H, 13.0, 10.2, H-6),
1.62 (q, 1H, 12.5, H-2), 13C-NMR (CDCl3,
δ ppm): 219.83 (C-6), 166.30, 166.05 (COO), 132.95, 132.84
(C-p), 129.98, 129.93 (C-q), 129.40, 129.22 (C-o), 128.31, 128.28 (C-m), 64.81 (C-8 or C-7), 63.73 (C-7 or
C-8), 51.90 (C-3a), 43.83 (C-1), 41.29, 41.20 (2C, C-3, C-6a), 39.66 (C-5), 30.76 (C-2), 22.16 (C-6), elem.
anal. calcd for C24H24O5, C: 73.45, H: 6.16, found: C: 73.90, H: 6.24.
3.14. PDC Oxidation of Alcohol 2c
The compound 2c (3.42 g, 5.1 mmol) was oxidized (as in 3.12) [CH2Cl2 (100 mL),
PDC (3 g), molecular sieves (3.8 g), r.t., 2 days]; TLC (II, Rf2c = 0.32, Rf5c = 0.57); 3.31 g
(97%) of pure 5c were obtained. By recrystallization from ethyl ether, 2.35 g of crystallized
(
±
)-(1
m.p. 189–191 C, IR (KBr): 3020, 2910, 2860, 1730, 1590, 1480, 1445, 1150, 1060, 750, 700 cm−1, 1H-NMR
(CDCl3, ppm, J Hz): 7.40 (dd, 12H, 7.9, 1.2, H-o), 7.28 (t, 12H, 7.9, H-m), 7.23 (tt, 6H, 7.9, 1.2, H-p),
α,3α,3aβ,6aβ)-1,2,3,3a,4,6a-1,3-bis((trityloxy)methyl)hexahydropentalen-5-one (5) were obtained,
◦
δ
3.13 (dd, 2H, 8.8, 5.8, H-7, H-8), 3.04–2.95 (m, 2H, H-3a, H-6a), 2.80 (t, 2H, 8.8, H-7, H-8), 2.57–2.45
(m, 2H, H-1, H-3), 2.06 (dd, 2H, 19.1, 9.5, H-4, H-6), 1.87 (dd, 2H, 19.1, 5.9, H-4, H-6), 1.82 (dt, 1H,
12.4, 6.2, H-2), 1.00 (q, 1H, 12.4, H-2), 13C-NMR (CDCl3,
δ ppm): 220.42 (C-5), 144.05 (6 Cq, Tr), 128.53
(12 C-m), 127.72 (12 C-o), 126.93 (6 C-p), 86.40 (2Cq, Tr), 64.30 (C-7, C-8), 41.75 (2C, C-3a, C-6a or C-1,
C-3), 40.88 (2C, C-1, C-3 or C-3a, C-6a), 38.76 (2C, C-4, C-6), 30.89 (C-2).

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3.15. Synthesis of (±)-(1α,3α,3aβ,6aβ)-1,2,3,3a,4,6,6a-Hexahydro-1H-spiro[pentalene-4,40-[1,3]dioxolane]-
1,3-diyl)bis(methylene)dibenzoate (11) from Ketone 5a
The symmetric ketone 5a (0.93g, 2.37 mmol) was dissolved in benzene (25 mL), ethylene glycol
(0.4 mL) and TsOH (10 mg) were added, and refluxed for 5 h (Dean-Stark trap for removing the
water) monitoring the reaction by TLC (VI, Rf5a = 0.69, Rf11 = 0.77). The reaction mixture was cooled,
washed with sat. sol. NaHCO3 (2
in quantitative yield by crystallization from benzene-hexane; the product has m.p. 99–100 C, IR (KBr):
3045, 2945, 2870, 1690, 1590, 1580, 1445, 1260, 1160, 1090, 1060, 1015, 960, 940, 870, 695 cm−1, 1H-NMR
×
20 mL), brine (20 mL), concentrated, and ketone 11 was obtained
◦
(CDCl3, δ ppm, J Hz): 8.04 (dd, 4H, 8.3, 1.2, H-o), 7.75 (tt, 2H, 7.2, 1.2, H-p), 7.44 (td, 4H, 8.3, 7.2, H-m),
4.40 (dd, 2H, 11.1, 6.8, H-7, H-8), 4.27 (dd, 2H, 11.1, 8.4, H-7, H-8), 3.92 (apparent t, 4H, O-CH2CH2-O),
2.90–2.83 (m, 2H, H-3a, H-6a), 2.55–2.46 (m, 2H, 6.8, 8.4, H-1, H-3), 1.91 (dt, 1H, 12.5, 5.3, H-2),
1.82 (dd, 2H, 12.7, 8.6, H4, H-6), 1.68 (dd, 2H, 12.7, 9.6, H-4, H-6), 1.32 (q, 1H, 12.5, H-2), 13C-NMR
(CDCl3,
δ ppm): 166.46 (COO), 132.93 (C-p), 130.54 (C-q), 129.60 (C-o), 128.40 (C-m), 117.86 (C-5),
65.54 (C-7, C-8), 64.91, 64.26 (OCH2CH2O), 41.14 (C-3a, C-6a or C-1, C-3), 41.03 (C-1, C-3 or C-3a, C-6a),
35.46 (C-4, C-6), 30.29 (C-2).
3.16. Synthesis of the Ethylene Ketal of the Unsymmetric Ketone 6a
The same reaction conditions: 6a (0.93 g, 2.37 mmol); TLC (VI, Rf5a = 0.69, Rf11 = 0.83). The crude
product (0.73 g) was purified similarly, resulting 605 mg (81.2%) of pure starting ketone 6a (IR and
NMR as for compound 6a).
3.17. Synthesis of Symmetrical Ketone 14 by Deprotection of the Benzoate Groups of 5a
To a soln. of bisbenzoate ketone 5a (0.4 g, 1.02 mmol) in methanol (30 mL), a solution
of MeONa (0.065 g/mL) (1 mL) was added and stirred at r.t. for 3 h, monitoring the
reaction by TLC (VII, Rf14 = 0.18).
Dowex 50 4, the filtrate was concentrated and the crude product was purified by
LPC (eluent, ethyl acetate–hexanes, 5:1), resulting a pure fraction of 165 mg (86.8%) of
)-(1 ,3 ,3a ,6a )-1,2,3,3a,4,6,6a-1,3-bis(hydroxymethyl)-hexahydropentalen-5-one (14) as an oil,
1H-NMR (DMSO-d6,
ppm, J Hz): 3.55 (dd, 2H, 10.7, 5.7, H-7, H-8), 3.27 (dd, 2H, 10.7, 7.4, H-7, H-8),
2.81–2.70 (m, 2H, H-3a, H-6a), 2.22–2.12 (m, 2H, H-1, H-3), 2.15 (dd, 2H, 18.5, 5.9, H-4, H-6), 2.07 (dd,
2H, 18.5, 9.5, H-4, H-6), 1.66 (dt, 1H, 12.5, 5.0, H-2), 1.11 (q, 1H, 12.5, H-2), 13C-NMR (DMSO-d6,
The base was neutralized with methanol-washed
×
(
±
α
α
β
β
δ
δ
ppm): 220.02 (C=O), 61.90 (2C, C-7, C-8), 42.92 (2C, C-1, C-3), 41.02 (2C, C-3a, C-6a), 38.36 (2C, C-4,
C-6), 30.07 (C-2).
3.18. Synthesis of (±)-(1α,3α,3aβ,6aβ)-1,2,3,3a,4,6,6a-Hexahydro-1H-spiro[pentalene-4,4'-[1,3]dioxolane]-
1,3-diyl)dimethanol (13)
Ethylene ketal 11 (0.49 g, 1.12 mmol) was hydrolyzed as described above for compound 5a
TLC (VII, Rf11 = 0.81, Rf13 = 0.20); LPC (ethyl acetate-hexane, 5:1); 235 mg (91.2%) of pure compound
13 were obtained as an oil, 1-H-NMR (CDCl3,
ppm, J Hz): 3.91 (m, 4H, OCH2CH2O), 3.59 (d, 4H,
7.4, H-7, H-8), 3.17 (br s, 2H, exchangeable with D2O, O ), 2.75–2.68 (m, 2H, H-3a, H-6a), 2.20–2.10
(m, 2H, H-1, H-3), 1.79 (dt, 1H, 12.4, 5.4, H-2), 1.72 (dd, 2H, 14.6, 8.5, H-4, H-6), 1.55 (dd, 2H, 14.6, 7.7,
H-4, H-6), 1.05 (q, 1H, 12.4, H-2), 13C-NMR (CDCl3,
ppm): 118.02 (C-5), 64.63, 63.95 (OCH2CH2O),
:
δ
H
δ
63.30 (2C, C-7, C-8), 44.32 (C-1, C-3), 40.73 (C-3a, 6a), 34.84 (2C, C-4, C-6), 30.02 (C-2).
3.19. Deprotection of Benzoate Groups of Compound 6a by Transesterification
The benzoate groups of the compound 6a (0.41 g, 1.04 mmol) were hydrolyzed by
transesterification, as described above (TLC, VII, Rf12 = 0.24, less active to dinitrophenylhydrazine);
to give 185 mg (quantitative yield) of (
6aH-pentaleno[1,6-bc]furan-6a-ol (15) as a cyclic hemiketal. The compound was crystallized from
±
)-(2aα,2a1α,4α,4aα,6aα)-4-(hydroxymethyl)octahydro-

Molecules 2017, 22, 2032
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◦
ethyl acetate, m.p. 106–108 C, IR: 3442, 3353, 3250, 2952, 2913, 2878, 2858, 1462, 1428, 1315, 1078,
1056, 1024, 981, 898, 790 cm−1, 1H-NMR (DMSO-d6,
ppm, J Hz): 5.75 (s, 1H, OH-4, exchangeable
δ
with D2O), 4.29 (t, 1H, 4.7, OH-8, exchangeable with D2O,), 3.82 (dd, 1H, 8.5, 4.8, H-7), 3.53 (d, 1H,
8.5, H-7), 3.28 (d, 2H, 7.3, H-8), 2.61 (t, 1H, 8.6, H-3a), 2.45–2.60 (m, 2H, H-6a. H-3), 1.96 (m, 1H, 6.6,
H-1), 1.86 (dd, 1H, 12.4, 6.5, H-5), 1.80 (m, 1H, 12.6, H-2), 1.54 (dt, 1H, 13.3, 6.5, H-6), 1.43 (dt, 1H, 13.3,
6.9, H-5), 1.25 (m, 1H, 12.4, 10.2, 6.0, H-6), 1.01 (td, 1H, 12.6, 8.9, H-2), 13C-NMR (DMSO-d6,
δ
ppm):
115.00 (C-4), 71.74 (C-7 ), 61.38 (C-8), 58.90 (C-3a), 47.16 (C-1), 44.14 (C-6a or C-3), 43.72 (C-3 or C-6a),
38.44 (C-5), 33.37 (C-2), 24.02 (C-6). 1H-NMR (CDCl3,
ppm, J ppm): 4.05 (dd, 1H, 8.8, 5.1, H-7),
δ
3.75 (d, 1H, 8.8, H-7), 3.58 (d, 2H, 7.3, H-8), 2.86 (t, 1H, 9.0, H-3a), 2.77–2.66 (m, 2H, H-3, H-6a), 2.15
(m, 1H, H-1), 2.05 (dd, 1H, 6.3, 12.4, H-6), 1.93 (ddd, 1H, 12.6, 8.4, 6.1, H-2), 1.78 (td, 1H, 12.5, 6.8,
H-5), 1.59 (dt, 1H, 12.5, 7.4, H-5), 1.43 (ddt, 1H, 11.7, 12.4, H-6), 1.20 (dt, 1H, 12.6, 9.6, H-2), 13C-NMR
(CDCl3,
δ ppm): 115.00 (C-5), 71.44 (C-7), 61.38 (C-8), 58.90 (C-3a), 47.16 (C-1), 44.14 (C-6a or C-3),
43.72 (C-3 or C-6a), 38.44 (C-5), 33.72 (C-2), 24.02 (C-6). The molecular structure was confirmed by
X-ray crystallography (Figure 7).
4. Conclusions
Hydroboration-oxidation of 2
the alcohols (symmetric) and (unsymmetric) in ~60% yield, together with the monobenzoate diol
4a (37%), resulting from by the reduction of the closer benzoate by the intermediate alkylborane.
Alkene and dialdehyde 10 gave only the triols and in ~1:1 ratio, in >73% yield. By increasing
the reaction time and the reaction temperature, the isomerization of alkylboranes favors the
un-symmetrical triol The mechanism of reduction of the closer ester to 4-alkylborane and
the isomerization of alkylboranes toward the unsymmetrical regioisomer were also presented.
The oxidation of the secondary alcohols cleanly gave the corresponding ketones and and the
α,4α-dimethanol-1β,5β-bicyclo[3.3.0]oct-6-en dibenzoate (1) gave
2
3
7
8
9
9.
5
6
deprotection of the benzoate groups gave the symmetrical ketone 14, and the cyclic hemiketal 15, all in
high yields. The ethylene ketals of the symmetrical ketones 11 and 13 were also obtained. In conclusion,
different symmetric and un-symmetric ketones and protected ketone compounds were synthesized.
They are potentially useful key intermediate for the synthesis of new carbacyclin and/or isocarbacyclin
analogues with different structural radicals. The structure of the compounds was established by NMR
spectroscopy and confirmed by X-ray crystallography.
Supplementary Materials: The Supplementary Material associated with this article (1H-NMR and 13C-NMR
spectra for compounds, crystallography data in Table S1 for compounds
Also CIF files and cifreport for compounds: (shI_3623-CoTa.cif),
15 (shI_1265-CoTa.cif) are available as Supplementary material.
8
,
3
,
5
and 15) are available online.
8
3
(shI_3624-CoTa.cif), (shI_3625-CoTa.cif) and
5
Acknowledgments: We thank the Romanian Ministry for Research and Innovations for funds to cover the cost of
publishing the article in open access.
Author Contributions: Constantin I. Tănase and Florea G. Cocu conceived and designed the experiments,
performed the experiments, and analyzed the data; Constantin I. Tănase and Constantin Drăghici wrote the paper;
Miron Teodor Căproiu, Constantin Drăghici did the physico-chemical studies of the synthesized compounds;
Sergiu Shova did the X-ray analysis.
Conflicts of Interest: The authors declare no conflict of interest.
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