Synthesis and the absolute configuration of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide as a new chiral building block for prostanoid synthesis

Article abstract of DOI:10.1039/c4ob01535e

The synthesis of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide (5) was accomplished in five steps starting from meso-tartaric acid (6). The key steps involved are preparation of the isopropylidene protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enone (9), resolution of the diastereoisomeric products 10 of the Horner reaction of racemic 9 with (R)-glyceraldehyde acetonide and the final regioselective ozonolysis of the exocyclic carbon-carbon double bond of the separated dienones 10 leading to both enantiomeric title compounds 5. The absolute configuration of both enantiomers was initially assigned based on the comparison of the chiroptical properties obtained from the DFT calculations with the experimental data and finally confirmed by X-ray analysis.

Full text of DOI:10.1039/c4ob01535e

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Page 1 of 11
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Synthesis and Absolute Configuration of Both Enantiomers of 4,5ꢀ
Dihydroxyꢀ3ꢀ(formyl)cyclopentꢀ2ꢀenone Acetonide as a New Chiral
Building Block for Prostanoid Synthesis
Beata Łukasik,a Marian Mikołajczyk,a Grzegorz Bujaczb and Remigiusz Żurawiński*a
The synthesis of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide (5) was accomplished
in five steps starting from meso-tartaric acid (6). The key steps involved preparation of the isopropylidene
protected
3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxy-cyclopent-2-enone
(9),
resolution
of
the
diastereoisomeric products 10 of the Horner reaction of racemic 9 with (R)-glyceraldehyde acetonide and final
regioselective ozonolysis of the exocyclic carbon-carbon double bond of the separated dienones 10 leading to
both enantiomeric title compounds 5. The absolute configuration of both enantiomers was initially assigned based
on the comparison of the chiroptical properties obtained from the DFT calculations with the experimental data
and finally confirmed by X-ray analysis.
Introduction
Prostaglandins are naturally occurring metabolites derived from oxidation of polyunsaturated fatty acids. These hormoneꢀ
like chemical messengers regulate a broad range of physiological activities in animals and man, including blood circulation,
the contraction and relaxation of smooth muscle tissue, inflammatory and pain mediation, digestion and reproduction.1
Moreover, prostaglandins of A and J series and their analogues characterized by the presence of a chemically reactive α,βꢀ
unsaturated carbonyl moiety show antineoplastic2 and neuroprotective3 activities. The complex structures of prostaglandins
together with their broad spectrum of biological activity have stimulated the development of new methods of their synthesis
for over 40 years.4 Currently, the prostaglandins and their analogues are prepared by three main basic strategies. In the first
one, the core cyclopentane bearing appropriate substituents is used as a precursor for further functionalization of αꢀ and ωꢀ
chains. In the second strategy (a twoꢀcomponent coupling), a fiveꢀmembered cyclic structure encompassing one of the two
side chains is first synthesized and the second chain (either the α or the ωꢀchain) is introduced at a later stage. The third
strategy (threeꢀcomponent coupling initiated and developed in Noyori’s group), a oneꢀpot procedure, involves a 1,4ꢀaddition
of the ωꢀchain to the appropriate cyclopentenone, followed by in situ trapping with the required αꢀchain component as an
electrophile.5 All these strategies are based mainly on such chiral substrates like Corey’s lactone and its derivatives 1, 4ꢀ
silyloxyꢀ or 4ꢀalkoxy derivatives of cyclopentꢀ2ꢀenone 2 and 4,5ꢀdihydroxy cyclopentꢀ2ꢀenone acetonide 3 (Fig. 1). The
syntheses of these cyclopentane and cyclopentene derivatives are often quite lengthy and based on the reagents which are
expensive and/or hardly available.
Fig. 1 The most frequently used intermediates in the prostaglandin synthesis.
As part of our research program aimed at the invention and development of general methods for the synthesis of bioactive
cyclopentenones and cyclopentanones using phosphorus reagents,6 the diastereoisomers of camphor protected 3ꢀ
[(dimethoxyphosphoryl)methyl]ꢀ4,5ꢀdihydroxycyclopentꢀ2ꢀenone 4 have been prepared7 and proposed as new chiral building
blocks in our strategy of the synthesis of various target compounds. Recently, their utility in the prostanoid synthesis has
been demonstrated by the preparation of both enantiomers of anticancer cyclopentenone prostaglandin analogue TEIꢀ9826.8
a Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza Str.
112, 90ꢀ363 Łódź, Poland, Fax: (+48)ꢀ42ꢀ680ꢀ32ꢀ60, Eꢀmail: remzur@cbmm.lodz.pl
b Institute of Technical Biochemistry, Technical University of Łódź, Stefanowskiego 4/10, 90ꢀ924 Łódź, Poland.

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Scheme 1 Synthesis of both enantiomers of TEI-9826.
To gain further flexibility in functionalization of the cyclopentenone ring and to overcome some limitations in the use of
the diastereoisomers of 4 (low diastereoselectivity of the cyclopentenone ring formation, tedious separation, steric bulk of the
camphor protecting group), we decided to synthesize both enantiomers of compound 5 (Fig. 2) and use them as substrates in
our planned syntheses of prostanoids. The presence of the formyl group at C3 allows to functionalize this position not only
by the Wittig reaction, as reported by Durand and coworkers in their synthesis of phytoprostane B1 type I and II methyl
esters,9 but also by the Peterson reaction and JuliaꢀKocienski method. Some other reactions of the C3ꢀformyl group may be
utilized as well.
Fig. 2 Structures of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide 5.
In this paper we report the synthesis of both enantiomers of the building block 5 and determination of their absolute
configuration by two methods: (a) by DFT calculations of their chiroptical properties (optical rotation and electronic circular
dichroism (ECD)) and (b) by Xꢀray structure determination of phenylhydrazone obtained from the dextrorotatory enantiomer
of 5.
Results and discussion
Synthesis of Enantiomeric 4,5ꢀcisꢀdihydroxyꢀ3ꢀ(formyl)cyclopentꢀ2ꢀenone acetonides (5)
The synthesis of both enantiomeric aldehydes 5 is outlined in Scheme 2. To have cisꢀarrangement of the two hydroxyl
groups at C4 and C5 in the cyclopentenone ring, a commercially available, optically inactive, mesoꢀtartaric acid (6) was used
as a starting material. Its acidꢀcatalyzed esterification with methanol gave the corresponding diester 7 which, in turn, was
efficiently converted into acetal 8 upon treatment with 2,2ꢀdimethoxypropane under acidic conditions. In the next step, the
reaction of the protected diester 8 with an excess of lithium salt of dimethyl methanephosphonate produced 3ꢀ
[(dimethoxyphosphoryl)methyl]ꢀ4,5ꢀdihydroxycyclopentꢀ2ꢀenone acetonide (9) in moderate yield. This cyclopentenone was
formally formed by the intramolecular Horner olefination of the bis(βꢀketophosphonate) A as the first intermediate product of
the above reaction. However, as we have showed earlier,10 the reaction course is more complex since the kinetically
controlled cyclopentenone B is initially formed from A as a result of the reversible Knoevenagel reaction. Addition of water
under basic reaction conditions to B allows its irreversible transformation into 9 which is the thermodynamically controlled
product of the condensation under discussion (Scheme 3). Therefore, the addition of 8 to the αꢀphosphonate carbanion was
carried out at low temperature and then, after addition of water, the reaction mixture was stirred at room temperature for 18 h.

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Scheme 2 Synthesis of (R,R)-5 and (S,S)-5.
Scheme 3 The reaction course between diester 8 and α-phosphonate carbanion.
Our approach to the synthesis of both enantiomers of 5 involves separation of the diastereoisomeric dienones obtained in the
Horner olefination reaction of 9 with a chiral aldehyde. With this in mind, Dꢀ(R)ꢀgliceraldehyde acetonide, easily available
from Dꢀmannitol by a bisacetalization/glycol cleavage sequence,11 has been chosen. The Horner reaction of 9 with Dꢀ(R)ꢀ
gliceraldehyde acetonide in the presence of DBU and lithium perchlorate afforded an equimolar mixture of diastereoisomeric
dienones 10a and 10b in a high yield. They were easily separated by column chromatography. In the final step, as expected,
selective ozonolysis of a more reactive exocyclic carbonꢀcarbon double bond in the diastereoisomers 10a and 10b carried out
with one equivalent of ozone in methanol at ꢀ78 oC gave rise to both enantiomers of aldehyde 5 in a good yield.
Theoretical Calculations of Chiroptical Properties of (R,R)ꢀ5
To assign absolute configuration of both enantiomers of aldehyde 5, theoretical calculations of their optical rotation and
electronic circular dichroism (ECD) were conducted. The principle of this approach is based on the comparison of the
calculated chiroptical properties with the experimental data. If the two data sets are very similar to each other, then highly
reliable assignment can be made. During the last several years numerous examples of a successful application of this
methodology in the determination of absolute configuration of a broad range of chiral species have been reported.12ꢀ15

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To calculate chiroptical properties of aldehyde 5, conformational search on an arbitrarily chosen enantiomer (R,R)ꢀ5 was
carried out employing MM+ force field.16 The obtained structures were fully optimized with the globalꢀhybrid functional
B3LYP17 in conjunction with the splitꢀvalence doubleꢀzeta polarized Pople 6ꢀ31G(d) basis set.18 These DFT calculations19
showed that in the energy range of 4 kcal/mole there are four stable conformers, 5aꢀd, in equilibrium at room temperature, as
a result of different orientation of the formyl group (sꢀcis or sꢀtrans) and the flap position of the acetal carbon atom in
adopted envelope conformation of the dioxolane ring (Fig. 3).
5a
5b
5c
5d
Fig. 3 Geometries of the stable conformers of (R,R)-5 calculated at the B3LYP/6-31G(d) level.
To include solvent effects in calculations of chiroptical properties, conformers 5 aꢀd were reoptimized at the B3LYP/6ꢀ
311++G(2d,2p)20 level applying the integral equation formalism of the polarizable continuum model (IEFPCM)21 for
methanol and dichloromethane (DCM). The harmonic vibrational frequencies of each conformation were calculated at the
same level to confirm their stability (no imaginary frequencies observed), and to evaluate the corresponding free energies.
Because the knowledge of the correct conformer populations is crucial for the proper prediction of the molecular chiroptical
properties, for all conformers more accurate singleꢀpoint energy calculations applying the doubleꢀhybrid density functional
with longꢀrange dispersion correction B2PLYPꢀD22 and Dunning’s correlationꢀconsistent polarized tripleꢀzeta with diffusion
functions augꢀccꢀpVTZ23 were performed to obtain a reliable Boltzmann distribution.
Based on the results of geometry optimizations singleꢀpoint optical rotation calculations of conformers 5aꢀd were
conducted at either 589.3 nm (sodium D line) and 546 nm wavelengths of incident light in methanol and dichloromethane
applying the four density functionals differing in the amount of HartreeꢀFock (HF) exchange: the globalꢀhybrid metaꢀGGA
M062X functional24 with 54% of HF exchange; the long range corrected CAMꢀB3LYP functional25 using the Coulombꢀ
attenuating method (19ꢀ65% of HF exchange); the rangeꢀseparated hybrid ωB97XD26 functional with dispersion correction
(22.2ꢀ100% of HF exchange) and the globalꢀhybrid GGA B3LYP17 functional (20% of HF exchange). The main goal of
conducting these calculations with the four functionals and under different conditions was to reach a higher level of
confidence in the assignment of absolute configuration of both enantiomers of aldehyde 5. Moreover, we also were interested
in comparison of the accuracy of the modern M062X, CAMꢀB3LYP and ωB97XD functionals with respect to the B3LYP
functional, which is still most popular in most areas of quantum chemistry despite its known shortcomings. The theoretical
specific rotation values were obtained as averages weighted on the Boltzmann population of conformers 5aꢀd estimated on
the basis of free energies (PꢁG) and on singleꢀpoint energies with thermal correction to free energy (PꢁE) (Table 1 and Table
2).

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Table 1. Experimental ((ꢀ)ꢀ5) and theoretical optical rotations of (R,R)ꢀ5 calculated in MeOH at the IEFPCM DFT/6ꢀ311++G(2d,2p) level at
598.3 and 546 nm wavelengths.
[α]D
[α]546
Pꢀ
Pꢀ
G
[%]a
E
Conformer
CAMꢀ
B3LYP
+33.6
ꢀ89.8
ꢀ43.6
ꢀ256.6
CAMꢀ
B3LYP
+44.8
ꢀ92.1
ꢀ48.8
ꢀ299.9
[%]b
B3LYP
M062X
B3LYP
M062X
ωB97XD
ωB97XD
5a
5b
5c
5d
65.9
53.2
+16.9
ꢀ115.9
ꢀ73.9
ꢀ341.0
ꢀ25.3
+35.0
ꢀ79.8
ꢀ41.2
ꢀ243.9
ꢀ0.1
+30.3
ꢀ97.3
ꢀ38.9
ꢀ256.3
ꢀ4.7
+25.6
ꢀ102.5
ꢀ77.6
ꢀ379.3
ꢀ20.0
+48.4
ꢀ75.3
ꢀ45.2
ꢀ280.3
+7.3
+41.2
ꢀ100.7
ꢀ41.6
ꢀ298.3
+0.4
9.7
21.7
2.6
6.8
36.3
3.7
ꢀ2.9
(ꢀ13.5)
+2.0
(ꢀ11.2)
Boltzmannꢀaveraged [α]c
(ꢀ38.3)
(ꢀ10.7)
(ꢀ14.1)
(ꢀ35.5)
(ꢀ6.1)
(ꢀ11.0)
ꢀ8.5 (c=1.7)
ꢀ3.8 (c=1.7)
Experimental [α]
a Populations based on ꢀG values at 298 K. b Population based on singleꢀpoint energy calculations at the B2PLYPꢀD/augꢀccꢀpVTZ level with
thermal correction to free energy. c Based on populations calculated on ꢀG and ꢀE (in parentheses) values.
Table 2. Experimental ((ꢀ)ꢀ5) and theoretical optical rotations of (R,R)ꢀ5 calculated in dichloromethane at the IEFPCM DFT/6ꢀ
311++G(2d,2p) level at 598.3 and 546 nm wavelengths.
[α]D
[α]546
Pꢀ
Pꢀ
G
[%]a
E
Conformer
CAMꢀ
B3LYP
+18.0
ꢀ52.0
ꢀ63.2
ꢀ245.7
CAMꢀ
B3LYP
+25.9
ꢀ42.4
[%]b
B3LYP
M062X
B3LYP
M062X
ωB97XD
ωB97XD
5a
5b
5c
5d
65.6
53.4
ꢀ3.8
ꢀ44.4
ꢀ109.5
ꢀ324.6
ꢀ39.9
+17.5
ꢀ35.7
ꢀ62.9
ꢀ230.6
ꢀ12.7
+14.3
ꢀ57.1
ꢀ58.7
ꢀ244.2
ꢀ16.7
ꢀ0.4
+1.6
ꢀ129.7
ꢀ353.2
ꢀ37.4
+26.5
ꢀ16.4
ꢀ73.8
ꢀ261.8
ꢀ7.7
+21.7
ꢀ47.8
ꢀ67.2
ꢀ281.8
ꢀ13.8
11.3
19.8
3.3
8.2
33.7
4.7
ꢀ74.1
ꢀ285.0
ꢀ14.7
(ꢀ37.0)
ꢀ11.9
(ꢀ27.9)
Boltzmannꢀaveraged [α]c
(ꢀ57.8)
(ꢀ25.6)
(ꢀ28.2)
(ꢀ60.3)
(ꢀ24.3)
(ꢀ28.1)
ꢀ20.8 (c=1)
ꢀ18.7 (c=1.0)
Experimental [α]
a Populations based on ꢀG values at 298 K. b Population based on singleꢀpoint energy calculations at the B2PLYPꢀD/augꢀccꢀpVTZ level with
thermal correction to free energy. c Based on populations calculated on ꢀG and ꢀE (in parentheses) values.
All the four methods agree that the individual conformers exhibit substantially different specific rotation regarding their
sign and magnitude. Thus, for example, the specific optical rotations of the conformers 5a and 5d calculated with the B3LYP
functional in methanol at the 589.3 nm wavelength were +16.9 and ꢀ341.0, respectively. It shows that although the population
of conformer 5d is relatively low (4.7ꢀ2.6% depending on the calculation methods and conditions) it has a great impact on
averaged optical rotation of (R,R)ꢀ5 which makes of special importance the proper estimation of conformers distribution for
accurate computations. In contrast to the B3LYP functional, which has a small HF exchange and does not have asymptotic
correction, Boltzmannꢀaveraged optical rotations calculated by the use of the M062X, CAMꢀB3LYP and ωB97XꢀD
functionals were close to the experimental values obtained for (ꢀ)ꢀ5.
The geometries of conformers 5aꢀd optimized at the IEFPCMꢀB3LYP/6ꢀ311++G(2d,2p) level in methanol were also
employed as the input geometries for the simulations of the ECD spectra by the TDꢀDFT method. Excitation energies and
rotatory strengths for the lowest 20 states have been calculated for each conformer with the 6ꢀ311++G(2d,2p) basis set and
the B3LYP, M062X, CAMꢀB3LYP and ωB97XD functionals applying IEFPCM solvent model for methanol. The theoretical
ECD spectra of (R,R)ꢀ5 were obtained by applying a 0.4 eV Gaussian shaped line width for each transition and taking into
account conformer populations based the on ꢁE values.27 In the ECD spectrum of (ꢀ)ꢀ5 recorded in methanol, a strong
negative Cotton effect is visible at 224 nm and a very broad weak positive band at 341 nm (Fig. 4). The calculated ECD
spectra of (R,R)ꢀ5 with the M062X, CAMꢀB3LYP and ωB97XD functionals reproduce well the experimental spectrum of (ꢀ)ꢀ
5 in term of the shape as well as the sequence of the negative/positive Cotton effects (Fig. 5). Both the (–/+) pattern are
clearly visible however, the peaks show a redshift to higher wavelengths and lower intensity with respect to the experimental
spectrum. The agreement is especially good when employing the M062X functional. In contrast, the B3LYP functional does
not give the right prediction of the sign and magnitude of the positive Cotton effect visible in the experimental spectrum of (ꢀ
)ꢀ5.

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Fig. 4 Experimental ECD spectra of (+)-5 and (-)-5 recorded in methanol.
Fig. 5 ECD spectrum of (-)-5 and simulated spectra of (R,R)-5 calculated at the IEFPCM TD-DFT/6-311++G(2d,2p) level in
methanol. The simulated spectra have been red-shifted by 16 nm in order to match the experimental trace.
Because the calculated chiroptical properties were in such a close agreement with the experimental results, it allowed us
to assign R,R absolute configuration to the levorotary enantiomer of 5 and S,S to the opposite one.
XꢀRay Analysis
To give definite proof of the right assignment of absolute configuration based on the theoretical calculations, (ꢀ)ꢀ5 was
selectively reduced with sodium triacetoxyborohydride to allyl alcohol 11 with the hope of obtaining suitable crystals for Xꢀ
ray diffraction analysis (Scheme 4).
O
O
NaBH(OAc)3
82%
O
O
OH
CHO
O
O
(-)-5
11
Scheme 4 Preparation of allyl alcohol 11.
In fact, alcohol 11 turned out to be solid, however, our attempts to obtain the good quality crystals failed. In our second
approach aldehyde (+)ꢀ5 was reacted with phenylhydrazine to give crystalline hydrazone 12 and dihydrazone 13 in the yield
of 38% and 35%, respectively (Scheme 5).
O
O
N
NHPh
O
O
(-)-12
PhNHNH2
O
EtOH, H2O
+
CHO
PhHNN
O
(+)-5
O
O
N
NHPh
(+)-13
Scheme 5 Synthesis of hydrazone 12.

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The suitable for Xꢀray analysis crystal of 12 was obtained by slow crystallization from ethanol. Xꢀray analysis of hydrazone
12 strongly suggested S absolute configuration of the stereogenic C4 and C5 carbon atoms which was in a full agreement
with the conclusions drawn from the theoretical calculations (Fig. 6). The determination of the absolute configuration of
compound 12 based on the analysis of the Friedel opposites28 required a precise diffraction experiment. There were 979
Friedel pairs out of total possible 1238 (for that data resolution), meaning that the Flack test should be meaningful. Random
errors in the data increased standard deviation of the Flack parameter, which in our refinement was ꢀ0.3(3) for the given
configuration and 1.2(3) for the opposite one, but in overall the determined absolute configuration of 12 is highly probable
.
Hydrazone 12 crystallized in P212121 group which is one of the most popular groups for chiral compounds. The shape of the
molecule is reflected in the unit cell dimensions with one short axis and two other approximately three times longer (Fig. 7).
The molecule of 12 has four possible proton acceptor groups and only one strong hydrogen donor from the hydrazone
moiety. The intermolecular hydrogen bonds are responsible for the crystal packing. The deficiency of strong donors was
compensated by carbon hydrogens. There are three hydrogen bonds in the crystal lattice: the first N2ꢀH2N...O1 with the
distance 2.12(1)Å, the second C6ꢀH61...O2 with the distance 2.45(1)Å, and third C12ꢀH121...O1 with the distance 2.56(1)Å.
The fourth contact with O3 as an acceptor is much weaker and the distance C14ꢀH141...O3 is 2.99(1) Å. The closest contact
to the acceptor atoms N1 is from hydrogen H151 connected to C15; this intermolecular hydrogen contact is 2.51(1) Å but the
angle C15ꢀH151...N1 is only 97.6(1) what reduces its strength.
Fig. 6 X-ray ORTEP plot of hydrazone 12. Displacement ellipsoids are shown at 50% probability level.
Fig. 7 X-ray structure of 12 showing intermolecular interactions.

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Conclusions
In conclusion, the short synthesis of both enantiomers of 4,5ꢀdihydroxyꢀ3ꢀ(formyl)cyclopentꢀ2ꢀenone acetonide (5) was
developed based on commercially available mesoꢀtartaric acid (6) as a starting material. The absolute configuration of
aldehyde 5 was assigned on the basis of the theoretical calculations of the optical rotation and electronic circular dichroism
and confirmed by Xꢀray analysis of hydrazone derivative of (+)ꢀ5. Calculations were conducted with four functionals under
different conditions. The best agreement of the theoretically calculated chiroptical properties with the experimental data was
observed for the M062X functional while the B3LYP functional did not give satisfactory results.
Experimental
General: Unless stated otherwise, all air and water sensitive reactions were carried out under an argon atmosphere using
freshly distilled dry solvents. All glassware was dried prior to use by heating under vacuum. Commercial grade reagents and
solvents were used without further purification except as indicated below. THF and diethyl ether were distilled over
Na/benzophenone prior to use. Ozone was generated using Fisher Ozone Generator 500. Thin layer chromatography (TLC)
was conducted on Silica Gel 60 F254 TLC purchased from Merck. Column chromatography was performed using Merck silica
gel (70ꢀ230 mesh). NMR spectra were recorded on Bruker AV 200, Bruker DRX 500 or Bruker Avance III 600
spectrometers. 1H, 13C and 31P chemical shifts are reported relative to the residual proton resonance in the deuterated solvents
or referred to an 85% aqueous solution of H3PO4, respectively. All chemical shifts (δ) are given in ppm and the coupling
constants (J) in Hz. HRMS were recorded on Finnigan MAT 95 apparatus. Optical rotations were measured using a Perkinꢀ
Elmer MC 241 photopolarimeter. Melting and boiling points are uncorrected.
ECD Spectra Recording: ECD spectra were recorded on a CD6 dichrograph (JobinꢀYvon, Longjumeau, France) at room
temperature using cells with 0.1 mm path length, 2 nm bandwidth, and 1ꢀ2 s integration time. Each spectrum was smoothed
with a 24ꢀpoint algorithm (included in the manufacturer’s software, version 2.2.1) after averaging at least three scans. Spectra
of (ꢀ)ꢀ5 and (+)ꢀ5 were recorded in methanol at concentration of 17.6 mM and 17.56 mM, respectively.
XꢀRay Crystal Structure Determination: The crystal data were recorded on an Oxford Xcalibur Onyx Nova singleꢀcrystal
diffractometer with Cu Kα radiation (λ = 1.5418 Å). To obtain the high resolution data with a good redundancy the 16 runs
under different theta and kappa angles were collected. Data collection, cell refinement and data reduction were performed
using the CrysAlis PRO program (Oxford Diffraction). The structure was solved by direct methods (OLEX2)29 and refined
using fullꢀmatrix leastꢀsquares difference Fourier techniques SHELX9730. The carbon hydrogens were set geometrically and
refined as riding, the hydrogen atom connected with nitrogen was found on the difference Fourier map and refined with
geometrical restrains. The anisotropic thermal parameters were applied for all the nonꢀhydrogen atoms and isotropic for
hydrogens, equal to 1.2 of the thermal parameter of their parental atoms. The absolute configuration was assigned based on
Flack parameters.
Computational Details: The preliminary conformational search was carried out on an arbitrarily chosen enantiomer (R,R)ꢀ5
using HyperChem16 and the MM+ molecular mechanics force field. All DFT and TDꢀDFT calculations were performed
using the ultrafine ("99,590") Lebedev grid and tight convergence criteria of the Gaussian 0919 program. For all conformers
5aꢀd optimized at the B3LYP/6ꢀ311++G(2d,2p) level in methanol and dichloromethane (IEFPCM solvent model) more
accurate IEFPCM B2PLYPꢀD/augꢀccꢀpVTZ singleꢀpoint energy calculations were performed to obtain a reliable Boltzmann
distribution. Calculations of chiroptical properties was carried out with the four density functionals (B3LYP, CAMꢀB3LYP,
M062X,
ωB97XD) in conjunction with the 6ꢀ311++G(2d,2p) basis set. The theoretical specific rotation values and ECD
spectra were obtained as averages weighted on the Boltzmann population of conformers 5aꢀd.
Dimethyl mesoꢀtartrate (7): A mixture of mesoꢀtartaric acid (6) (315.0 g, 2.1 mol), methanol (100 mL), benzene (1000 mL)
and pꢀtoluenesulfonic acid monohydrate (1.5 g, 7.88 mmol) was refluxed for 20 h. The water formed was distilled off as an
azeotrope with benzene and methanol which was successively added (8 x 50 mL). Then, methanol (200 mL) was added and
the solution was cooled to room temperature. Anhydrous potassium carbonate (3 g) was added and the mixture was stirred for
15 minutes. The solution was filtered and the solvents were evaporated to afford 7 (305.5 g, 88%) as a colorless solid. mp
°
1
113ꢀ114 C. H NMR (200 MHz, CDCl3): δ 4.57 (s, 2 H, CH), 3.80 (s, 6 H, CH3), 3.37 (s, 2 H, OH). 13C NMR (50 MHz,
CDCl3): δ 171.36 (COOCH3), 72.91 (CH), 52.92 (OCH3). C6H10O6 (178.14): calcd. C 40.45, H 5.66; found C 40.32, H 5.71.
Dimethyl O,Oꢀisopropylidenetartrate (8):
A mixture of dimethyl mesoꢀtartrate (7) (20.0 g, 0.112 mol), 2,2ꢀ
dimethoxypropane (25.5 g, 0.244 mol), dry methanol (9 mL) and pꢀtoluenesulfonic acid monohydrate (0.18 g, 1 mmol) was
°
heated at 70 C under an argon atmosphere for 1 h. The dark red solution was cooled to room temperature and dry
cyclohexane (45 mL) was added. Methanol and acetone were removed under gentle reflux (c.a. 37 mL). Next, 2,2ꢀ
dimethoxypropane (5.1 g, 0.049 mol) and dry cyclohexane (10 mL) were added and the solution was refluxed for 2 h. After
cooling down to room temperature anhydrous potassium carbonate (1 g) was added. The solution was filtered and the crude
product was purified by distillation under reduced pressure (78 °C, 0.1 mmHg) to give 8 (21.1 g, 86%) as a colorless liquid.
1H NMR (600 MHz, CDCl3): δ 4.84 (s, 2 H, CH), 3.75 (s, 6 H, OCH3), 1.65 (s, 3 H, CꢀCH3), 1.41 (s, 3 H, CꢀCH3). 13C NMR
(151 MHz, CDCl3): δ 174.60 (COOCH3), 113.08 (OꢀCꢀO), 76.29 (CH), 52.51 (OCH3), 26.59 (CH3C), 25.75 (CH3C). HRMS
(EI) calcd. for C8H11O6 [M ꢀ CH3]+ 203.0556, found 203.0554. C9H14O6 (218.20): calcd. C 49.54, H 6.47; found C 49.68, H
6.55.

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4,5ꢀDihydroxyꢀ3ꢀ[(dimethoxyphosphoryl)methyl]cyclopentꢀ2ꢀenone acetonide (9): To a stirred solution of dimethyl
methanephosphonate (15.3 g, 123.7 mmol) in THF (400 mL) at ꢀ78 °C nꢀBuLi (49.9 mL, 2.37 M in hexane, 118 mmol) was
added. Stirring was continued for 0.5 h and dimethyl O,Oꢀisopropylidenetartrate (8) (6.0 g, 27.5 mmol) in THF (20 mL) was
added. After 1 h the cooling bath was removed, and the mixture was allowed to warm to room temperature. Then, THF was
evaporated under reduced pressure, water (200 mL) was added and the resulting solution was stirred for 18 h. The mixture
was neutralized with an aqueous solution of 5% hydrochloric acid and extracted with CHCl3 (4 x 150 mL). The organic layer
was dried over anhydrous MgSO4. The solvent was evaporated, and the crude product was purified by column
chromatography (petroleum ether/acetone 3:1) to yield 9 (5.9 g, 42%) as a colorless oil. 31P NMR (243 MHz, CDCl3): δ
1
24.72. H NMR (600 MHz, CDCl3): δ 6.10 (d, JPH = 4.3, 1 H, C(O)ꢀCH=C), 5.23 (dd, JHH = 5.4, JPH = 3.0, 1 H, C(O)ꢀCHꢀ
CHꢀO), 4.48 (d, JHH = 5.5, 1H, C(O)ꢀCHꢀO), 3.79 (d, JPH = 11.2, 3 H, OCH3), 3.80 (d, JPH = 11.1, 3 H, OCH3), 3.15ꢀ3.00 (m,
2 H, CH2), 1.40 (s, 3 H, CH3C), 1.37 (s, 3 H, CH3C). 13C NMR (151 MHz, CDCl3): δ 201.29 (d, JPC = 2.9, C=O), 166.89 (d,
J
PC = 10.2, C(O)ꢀCH=C), 132.16 (d, JPC = 9.1, C(O)ꢀCH=C), 115.44 (s, OꢀCꢀO), 80.05 (d, JPC = 4.0, C(O)ꢀCHꢀCHꢀO), 77.55
(s, C(O)ꢀCHꢀO), 53.19 (d, JPC = 6.7, CH3O), 52.99 (d, JPC = 6.6, CH3O), 27.62 (d, JPC = 137.4, CH2ꢀP), 27.30 (s, CH3C),
26.17 (s, CH3C). HRMS (EI) calcd. for C10H14O6P [M ꢀ CH3]+ 261.0528, found 261.0528. C11H14O6P (276.22): calcd. C
47.83, H 6.20; found C 48.02, H 6.19.
Synthesis of diastereoisomers 10a and 10b: Phosphonate 9 (1.5 g, 5.43 mmol) and lithium perchlorate (0.628 g, 5.89
mmol) were dissolved in THF (5 mL) and cooled to 0 °C. 1,8ꢀDiazabicycloꢀ[5.4.0]undecꢀ7ꢀene (DBU, 0.9 g, 5.89 mmol) was
added and the mixture was stirred for 15 min. (R)ꢀglyceraldehyde acetonide (0.893 g, 6.86 mmol) in THF (1.5 mL) was
added and the resulting solution was stirred at 0ꢀ5 °C for 3 h. After evaporation of the solvent under reduced pressure, the
residue was subjected to column chromatography (petroleum ether: diethyl ether – 1.3:1) affording 10a (0.61 g, 40%) and
10b (0.58 g, 38%) as yellowish oils. 10a (less polar): [α]D22 +124 (c 1.6 in CH2Cl2). 1H NMR (600 MHz, CDCl3): δ 6.75 (d, J
= 15.8, 1 H, C(O)ꢀCH=CꢀCH=CH), 6.56 (dd, J = 15.8, J = 6.1, 1 H, C(O)ꢀCH=CꢀCH=CH), 6.00 (s, 1 H, C(O)ꢀCH), 5.32 (d,
J = 5.7, 1 H, C(O)ꢀCHꢀO), 4.71 (q, J = 6.4, 1 H, CH2ꢀCHꢀCH), 4.52 (d, J = 5.7, 1 H, C(O)ꢀCHꢀCHꢀO), 4.21 (dd, J = 8.2, J =
6.6, 1 H, CHAHX), 3.72 (t, J = 7.7, 1 H, CHAHX), 1.47 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3). 13C NMR (151 MHz, CDCl3): δ 202.26 (C=O), 167.13 (C(O)ꢀCH=C), 140.08 (C(O)ꢀCH=CꢀCH=CH), 129.65 (C(O)ꢀ
CH), 125.55 (C(O)ꢀCH=CꢀCH=CH), 115.21 (C(O)ꢀCHꢀOꢀC(CH3)2ꢀO), 110.13 (CH2ꢀOꢀC(CH3)2ꢀO), 77.89 (C(O)ꢀCHꢀCHꢀ
O), 77.53 (C(O)ꢀCHꢀO) , 75.93 (CH2ꢀCHꢀO), 69.03 (OꢀCH2), 27.29 (CH3), 26.53 (CH3), 26.08 (CH3), 25.68 (CH3). C15H20O5
(280.32): calcd. C 64.27, H 7.19; found C 64.05, H 7.29. 10b: [α]D22 ꢀ 58,5 (c 1.7 in CH2Cl2). 1H NMR (500 MHz, CDCl3): δ
6.75 (d, J = 15.9, 1 H, C(O)ꢀCH=CꢀCH=CH), 6.60 (dd, J = 15.8, J = 5.7, 1 H, C(O)ꢀCH=CꢀCH=CH), 6.01 (s, 1 H, O=Cꢀ
CH=C, C(O)ꢀCH), 5.31 (d, J = 5.7, 1 H, OꢀCHꢀC=O), 4.72 (q, J = 6.5, 1 H, CH2ꢀCHꢀCH), 4.52 (d, J = 5.7, 1 H, C(O)ꢀCHꢀ
CHꢀO), 4.21 (dd, J = 8.1, J = 6.5, 1 H, CHAHXꢀO), 3.71 (t, J = 7.8, 1 H, CHAHXꢀO), 1.49 (s, 3 H, CH3), 1.43 (s, 6 H, CH3),
1.37 (s, 3 H, CH3). 13C NMR (126 MHz, CDCl3): δ 202.27 (C=O), 167.26 (C(O)ꢀCH=C), 140.11 (C(O)ꢀCH=CꢀCH=CH),
129.55 (C(O)ꢀCH), 125.09 (C(O)ꢀCH=CꢀCH=CH), 115.27 (C(O)ꢀCHꢀOꢀC(CH3)2ꢀO), 110.13 (CH2ꢀOꢀC(CH3)2ꢀO), 77.90,
77.63, 75.86 (CH2ꢀCHꢀO), 69.12 (CH2O), 27.34 (CH3), 26.53 (CH3), 26.16 (CH3), 25.76 (CH3). C15H20O5 (280.32): calcd. C
64.27, H 7.19; found C 64.03, H 7.14.
(S,S)ꢀ(+)ꢀ4,5ꢀDihydroxyꢀ3ꢀ(formyl)cyclopentꢀ2ꢀenone acetonide ((S,S)ꢀ5): A solution of dienone 10b (0.148 g, 0.528
mmol) in anhydrous methanol (15 mL) was cooled to ꢀ78 °C and ozone (0.025 g, 0.528mmol) stream was passed through a
reaction mixture. Dimethyl sulfide (0.109 g, 1.71 mmol) was added, the cooling bath was removed and the solution was
allowed to warm to room temperature. After 2 h the solvent was removed in vacuo and the crude product was purified by
column chromatography (petroleum ether: acetone – 20:3.5) to yield (S,S)ꢀ5 (69 mg, 72%) as a light yellow oil. [α]D22 +21.5
(c 1.1 in CH2Cl2). [α]D22 +8,8 (c 1 in MeOH). 1H NMR (500 MHz, CDCl3): δ 10.23 (s, 1 H, CHO), 6.75 (s, 1 H, C=CH), 5.49
(d, J = 5.6, 1 H, OꢀCHꢀC=O), 4.61 (d, J = 5.6, 1 H, OꢀCHꢀCꢀCHO), 1.43 (s, 3 H, CH3), 1.40 (s, 3 H, CH3). 13C NMR (126
MHz, CDCl3): δ 202.34 (CO), 189.13 (CHO), 162.36 (CꢀCHO), 140.03(C=CH), 116.37((CH3)2C), 77.80 (OꢀCHꢀCꢀCHO) ,
75.26 (OꢀCHꢀC=O), 27.05 (CH3), 25.61 (CH3). HRMS (EI) calcd. for C9H10O4 182.0579, found 182.0576.
(R,R)ꢀ(ꢀ)ꢀ4,5ꢀDihydroxyꢀ3ꢀ(formyl)cyclopentꢀ2ꢀenone acetonide ((R,R)ꢀ5): According to the procedure described above,
23
10a (0.124 g, 0.442 mmol) was transformed into aldehyde (R,R)ꢀ5 (0.061 g, 76%). Pale yellow oil. [α]D ꢀ20.8 (c 1 in
CH2Cl2). [α]D23 ꢀ8,5 (c 1.7 in MeOH). HRMS (EI) calcd. for C9H10O4 182.0579, found 182.0577.
(
R,R)ꢀ(ꢀ)ꢀ4,5ꢀDihydroxyꢀ3ꢀ(hydroxymethyl)cyclopentꢀ2ꢀenone acetonide (11): To a stirred suspension of sodium
borohydride (0.301 g, 7.9 mmol) in dry benzene (40 mL) acetic acid (1.551 g, 0.026 mol) in dry benzene (5 mL) was slowly
added. The mixture was refluxed for 0.5 h and transferred to a solution of aldehyde (R,R)ꢀ5 (0.181 g, 0.994 mmol) in dry
benzene (2 mL). After 5 min of gentle heating the reaction mixture was cooled down to room temperature and filtered
through a silica gel pad. The solvent was evaporated and a crude mixture was purified by column chromatography (petroleum
ether : acetone ꢀ 2:1) to give 11 (0.141 g, 82%) as a colorless solid. mp 63ꢀ64 °C. [α]D25 ꢀ22.9 (c 1 in CH2Cl2). 1H NMR (500
MHz, CDCl3): δ 6.15 (s, 1 H, C=CH), 5.11 (d, J = 5.0, 1 H, OꢀCHꢀC=O), 4.68 (d, J = 18.5, 1 H, CH2OH), 4.52 (d, J = 18.5, 1
H, CH2OH), 4.49 (d, J = 5.0, 1 H, OꢀCHꢀCꢀCH2), 2.63 (s, 1 H, OH), 1.38 (s, 6 H, CH3). 13C NMR (126 MHz, CDCl3): δ
201.97 (CO), 176.74 (C=CꢀCH2), 127.46 (C=CH), 115.59 ((CH3)2C), 77.89 (OꢀCHꢀCꢀCH2), 77.79 (OꢀCHꢀC=O), 60.94
(CH2), 27.28 (CH3), 26.01 (CH3). HRMS (EI) calcd. for C9H12O4 184.0736, found 184.0729. C9H12O4 (184.19): calcd. C
58.69, H 6.57; found C 58.73, H 6.61.
(
S,S)ꢀ(ꢀ)ꢀ4,5ꢀDihydroxyꢀ3ꢀ[(phenylhydrazyl)methyl]cyclopentꢀ2ꢀenone acetonide (12): To a stirred suspension of
phenylhydrazine hydrochloride (0.087 g, 0.605 mmol) in ethanol (2 mL) was added sodium acetate (0.116 g, 1.414 mmol) in
water (0.5 mL). To a clear, pale yellow solution was added aldehyde (S,S)ꢀ5 (0.092 g, 0.504 mmol) in ethanol (1 mL), and the
reaction mixture was stirred for 0.5 h. Then, the solvents were evaporated, water (5 mL) was added, and the mixture was

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extracted with CHCl3 (3 x 20 mL). The organic layer was dried over anhydrous Na2SO4. The solvent was evaporated, and a
mixture was purified by flash chromatography (chloroform:ethyl acetate – 100:1) to afford hydrazone (S,S)ꢀ12 (52 mg, 38%)
as a reddishꢀorange solid and dihydrazone 13 (64 mg, 35%) as a yellowishꢀorange solid. The suitable for Xꢀray diffraction
analysis single crystal of 12 was obtained by its slow crystallization from ethanol. 12 (more polar): mp 187ꢀ189 °C. [α]D23 ꢀ
23.2 (c 0.9 in CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 8.54 (s, 1 H, NH), 7.68 (s, 1 H, CH=N), 7.32 (t, J = 7.9, 2 H, CArꢀH),
7.17 (d, J = 7.7, 2 H, CArꢀH), 7.00 (t, J = 7.4, 1 H, CArꢀH), 6.08 (s, 1 H, C=CH), 5.63 (d, J = 5.7, 1 H, OꢀCHꢀC=O), 4.57 (d, J
= 5.7, 1 H, OꢀCHꢀCꢀCH=N), 1.49 (s, 3 H, CH3), 1.43 (s, 3 H, CH3). 13C NMR (126 MHz, CDCl3): δ 202.61 (C=O), 165.59
(CꢀCH=N), 142.43 (NHꢀCAr), 130.38 (CH=N), 129.42 (CArꢀH), 126.96 (C=CH), 122.52 (CArꢀH), 114.88 ((CH3)2C), 113.93
(CArꢀH), 78.03 (OꢀCHꢀC), 76.91 (OꢀCHꢀC=O), 27.44 (CH3), 26.17 (CH3). HRMS (EI) calcd. for C15H16N2O3 272.1161,
found 272.1164. 13: mp 201ꢀ202 °C. [α]D23 +697.6 (c 0,6 in CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 8.30 (s, 1 H, NHꢀPh),
7.82 (s, 1 H, NHꢀPh), 7.56 (s, 1 H, CH=N), 7.28ꢀ7.23 (m, 4 H, CArꢀH), 7.09 (d, J = 7.7, 2 H, CArꢀH ), 7.07 (d, J = 7.7, 2 H,
CArꢀH), 6.87 (t, J = 7.3, 2 H, CArꢀH), 6.37 (s, 1 H, C=CH), 5.61 (d, J = 6.2, 1 H, OꢀCHꢀC=O), 5.20 (d, J = 6.2, 1 H, OꢀCHꢀCꢀ
CH=N), 1.51 (s, 3 H, CH3), 1.40 (s, 3 H, CH3). 13C NMR (126 MHz, CDCl3): δ 151.06 (N=C), 145.21 (NHꢀCAr), 144.46
(NHꢀCAr), 143.67 (CArꢀH), 132.98 (CH=N), 130,04 (C=CH), 129.24 (CArꢀH), 129.22 (CArꢀH), 120.73 (CArꢀH), 120.39 (CArꢀ
H), 114.06 ((CH3)2C), 113.09 (CArꢀH), 113.00 (CArꢀH), 80.03 (OꢀCHꢀC=N), 75.22 (OꢀCHꢀCꢀCH=N), 27.55 (CH3C), 27.40
(CH3C). HRMS (EI) calcd. for C21H22N4O2 362.1743, found 362.1742.
Crystal data of 12: orthorhombic, C15H16N2O3, space group P212121, a =5.6153(1) Å, b = 14.7472(3) Å, c = 16.9257(4) Å, V
= 1401.71(5) Å3, Z = 4, Dcalcd = 1.290 g/cm3, ꢂ = 0.747 mmꢀ1, and F(000) = 576. Crystal size: 0.34 × 0.23 × 0.18 mm.
Independent reflections: 2722 [Rint = 0.0881]. The final indices were R1 = 0.0566, wR2 = 0.1588 for 2432 reflections with I
> 2σ(I) and R1 = 0.0615, wR2 = 0.1745 for all reflections. The asymmetric unit contains one molecule of 12. The Flack
parameter is ꢀ0.3(3) for 12, and 1.2(3) for the reverse model in SHELX97. Crystallographic data of (ꢀ)ꢀ12 have been deposited
with the Cambridge Crystallographic Data Centre. CCDCꢀ1011113 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We gratefully acknowledge financial support from the Ministry of Science and Higher Education of Poland (related to grant
number N N204 12937.
Notes and references
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